CN1070646A - Imidazo-fused iso and heterocycle, their preparation method contains their composition and their application - Google Patents
Imidazo-fused iso and heterocycle, their preparation method contains their composition and their application Download PDFInfo
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- CN1070646A CN1070646A CN92110562A CN92110562A CN1070646A CN 1070646 A CN1070646 A CN 1070646A CN 92110562 A CN92110562 A CN 92110562A CN 92110562 A CN92110562 A CN 92110562A CN 1070646 A CN1070646 A CN 1070646A
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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Abstract
The following formula compound has very strong activity as angiotensin II receptor antagonists, and The compounds of this invention can be used as medicine or diagnostic reagent.Wherein to have following meaning: X be the monocyclic groups that 3,4 or 5 annular atomses are arranged to each symbol, and R (1), R (2), R (3), R (4), R (12) and R (13) are for example alkyl, and q is 0 or 1, and L is for example methylene radical, and A is for example heterocyclic radical.The compounds of this invention can be used as medicine or diagnostic reagent.
Description
European patent application 399,731,399,732,400,835 and 434,038 discloses the imidazo-fused aromatic substance as Angiotensin.But, do not have in the above-mentioned document one piece relate on the nitrogen-atoms of imidazole ring a substitution in ring is arranged simultaneously phenyl ring as substituting group and a heterocycle that is fused on this imidazole ring is arranged; Following compound almost is not disclosed or proposes: with a same aromatic substance that is fused on the imidazoles, an xenyl is arranged simultaneously on the nitrogen-atoms of imidazoles, and same, on xenyl, there is the compound of sulfonylurea or alkylsulfonyl urethane group also not appear in the newspapers.
We have found that now imidazole derivative of the present invention has the active antagonistic action of extra-high-speed to angiotensin in vitro and in vivo.
The present invention relates to the salt that can tolerate on following formula: compound and the physiology thereof,
Wherein each symbol has following meaning:
X is the bicyclic group that the monocycle base of 3,4 or 5 annular atomses is arranged or 8-10 annular atoms arranged, and monocycle base or bicyclic group can completely or partially be hydrogenated, wherein CH more than 1 or 1 or CH
2Group can be replaced by N, NH or O;
R(1) be: 1.(C
1-C
10) alkyl
2.(C
3-C
10) alkenyl,
3.(C
3-C
10) alkynyl,
4.OR（6），
5.(C
3-C
8) cycloalkyl,
6.(C
4-C
10) cycloalkylalkyl,
7.(C
5-C
10) the cycloalkyl alkenyl,
8.(C
5-C
10) the cycloalkyl alkynyl,
9.（CH
2）m-B-（CH
2）n-R（7），
10. benzyl,
11. the group of definition in top 1,2,3 or 9, this group is by CO
2R(6) the single replacement,
12. the group of definition in top 1,2,3 or 9, wherein 1～all hydrogen atoms are replaced by fluorine, perhaps
13. the group of definition in top 10 replaces by being selected from 1 of following series or 2 identical or different groups on the phenyl of this group: halogen, (C
1-C
4) alkoxyl group and nitro;
R(2), R(3), R(4) and R(5) can be identical or different, they are
1. hydrogen, halogen, hydroxyl, cyano group, nitro, sulfo group, formyl radical, benzoyl, (C
1-C
8) acyl group, (C
1-C
8) acyloxy, sulfydryl, carboxyl, (C
1-C
4) alkoxy carbonyl,
2. alkyl, alkenyl, alkoxyl group or allyl sulfenyl straight or branched, that replace arbitrarily up to 6 carbon atoms are arranged,
3. aryl, aralkyl or aromatic yl alkenyl, wherein alkyl and alkenyl substitutents have up to 6 carbon atoms and are the form of non-side chain or side chain, aryl substituent is that the monocyclic groups of 5 or 6 annular atomses is arranged or is the fused rings that 8-14 annular atoms arranged, wherein contain 1 or 1 above heteroatoms (as O, N or S), and at random be substituted
R(6) be 1. hydrogen,
2.(C
1-C
8) alkyl,
3.(C
3-C
8) cycloalkyl,
4. phenyl,
5. benzyl, perhaps
6. the group of definition in top 2, wherein 1～all hydrogen atoms are replaced by fluorine
R(7) be 1. hydrogen,
2.(C
1-C
6) alkyl
3.(C
3-C
8) cycloalkyl
4.(C
2-C
4) alkenyl, or
5.(C
2-C
4) alkynyl;
R(8) with R(9) or R(10) with R(11) or identical, or different, they can be
1. hydrogen,
2.(C
1-C
6) alkyl or (C
1-C
6) alkenyl, can be unsubstituted, perhaps by halogen, hydroxyl or (C
1-C
6) the alkoxyl group replacement,
3. aryl or (C
1-C
6) alkylaryl, wherein aryl is the monocycle that 5 or 6 annular atomses are arranged, perhaps for the dicyclo of 8-10 annular atoms is arranged, monocycle or dicyclo at random contain the heteroatoms (as O, N and S) more than 1 or 1, and can replace by being selected from 1 of following series or 2 identical or different groups: halogen, hydroxyl, nitro, (C
1-C
6) alkyl, (C
1-C
6) alkenyl, (C
1-C
4) alkanoyl, (C
1-C
4) alkanoyloxy and CO
2R; Perhaps
R(8) with R(9) or R(10) with R(11) form quaternary～eight yuan saturated or undersaturated ring with the nitrogen-atoms that is connected them, this ring can contain the other heteroatoms that is selected from N, O and S, and this ring can be unsubstituted, perhaps by halogen, hydroxyl, (C
1-C
4) alkyl, (C
1-C
4) alkenyl, (C
1-C
4) alkoxyl group and CO
2R(6) replace, perhaps
R(10) with R(11) be identical or inequality, can be acyl group or the (C that has up to 6 carbon atoms
1-C
6) alkyl or (C
6-C
12) aryl, they can be at random by halogen or (C
1-C
6) the alkyl replacement; L is (C
1-C
3) alkane 2 basis;
R(12) and R(13) be identical or different, can be
1. hydrogen,
2. halogen,
3. nitro,
4.(C
1-C
4) alkyl, perhaps
5.(C
1-C
2) alkoxyl group;
Q is zero or 1;
A 1. has the heterocyclic radical of 5-10 annular atoms, this heterocycle can be monocycle or dicyclo, and having up to 9 annular atomses in the heterocycle is carbon atoms, and this heterocyclic radical can be unsubstituted, perhaps by replacing, perhaps up to 6 (preferably up to 3) identical or different radicals R (14) with R(15)
2. unsubstituted or by up to 4 (preferably up to 2) identical or different radicals R (14) and the xenyl that R(15) replaces, but herein A must be at least by 1 at R(15) 18,19,28,40 or 42 in the group of definition replace, and q is zero
R(14) be 1. halogens
2. oxygen,
3. nitroso-group,
4. nitro
5. amino
6. cyano group
7. hydroxyl
8.(C
1-C
6) alkyl
9.(C
1-C
4) alkanoyl
10.(C
1-C
4) alkanoyloxy
11.CO
2R（6）
12. methanesulfonamido
13. fluoroform sulfonamido
14.-CO-NH-OR（16）
15.-SO
2-NR（17）R（18），
16.-CH
2-OR（18），
17.(C
1-C
4) heteroaryl-(CH
2) q-, 1-tetrazyl preferably,
18.(C
7-C
13) aroyl,
19.
20.
21.(C
6-C
12) aryl;
R(15) be 1. hydrogen,
2.(C
1-C
6) alkyl,
3.(C
3-C
8) cycloalkyl,
4.(C
6-C
12) aryl,
5.(C
7-C
13) aroyl,
6.(C
1-C
4) alkoxyl group,
7.(C
1-C
4) alkanoyloxy,
8.(C
1-C
9) heteroaryl,
9.CO
2R（6），
10. halogen
11. cyano group,
12. nitro,
13.NR（17）R（18）
14. hydroxyl,
15.-CO-NH-CHR（19）-CO
2R（6），
16. sulfo group,
17.-SO
3R（6），
18.-SO
2-NR(18)-CO-NR(17) R(16) ,-SO
2-NR(18)-CO-O-R(17) ,-SO
2N(CO-O-R(17))
2Or-SO
2-NR(18)-CS-NR(17) R(16),
19.-NR（18）CO-NR（17）-SO
2-CH
2-R（18），
20.-C（CF
3）
2OH，
21. phosphonato,
22.-PO
3H
2，
23.-NH-PO（OH）
2，
24.-S（O）
rR（17），
25.-CO-R（20），
26.-CO-NR（17）R（16），
27.
28.
29.
30.
31.5-tetrazyl-NH-CO-,
32.-CO-NH-NH-SO
2-CF
3，
39.-CO-NH-SO
2-R（6），
40.-SO
2-NH-CO-R（17），
41. the group of definition in 4, this group can replace by being selected from 1 of following series or 2 identical or different groups: halogen, cyano group, nitro, NR(17) R(18) and hydroxyl,
42.R(15) with R(14) formation-CO-NH-SO
2-;
R(16) and R(17) be identical or different, they are
1. hydrogen,
2.(C
1-C
6) alkyl,
3.(C
3-C
8) cycloalkyl,
4.(C
6-C
12) aryl, phenyl preferably,
5.(C
6-C
10) aryl-(C
1-C
4) alkyl,
6. part or all of hydrogenant (C
1-C
9) heteroaryl, preferably 2-pyrimidyl, piperidino or quinuclidinyl,
7.(C
3-C
6) alkanoyl,
8. by 1 or 2 identical or different group that is selected from following series: hydroxyl, methoxyl group, nitro, cyano group, CO
2R(6), trifluoromethyl ,-NR(25) R(26) and
What replace is defined in group in 4,5,6,9,14,15,16,18,19 or 20,
9.(C
1-C
9) heteroaryl-(C
1-C
3) alkyl, heteroaryl moieties can partly or entirely be hydrogenated here.
10.2 the group of middle definition, wherein 1-all hydrogen atom is replaced by fluorine,
11.(C
2-C
6) alkenyl,
12.(C
3-C
8) cycloalkenyl,
13.(C
3-C
8) cycloalkenyl-(C
1-C
3) alkyl,
14.(C
3-C
8) cycloalkyl-(C
1-C
4) alkyl,
15.(C
6-C
10) aryl-(C
3-C
6) alkenyl,
16.(C
1-C
9) heteroaryl-(C
3-C
6) alkenyl,
17.(C
3-C
6) alkynyl,
18.(C
6-C
10) aryl-(C
3-C
6) alkynyl,
19.(C
1-C
9) heteroaryl-(C
3-C
6) alkynyl,
20. formula
Group, R(16 in the formula) can not there be stereocenter for defining 20, perhaps be the R-configuration, perhaps be the S-configuration.
21.R(16) R(17) forming heteroaryl with the nitrogen-atoms that connects them, this heteroaryl is partly or entirely hydrogenation also;
R(18) be 1. hydrogen,
2.(C
1-C
6) alkyl,
3.(C
3-C
8) cycloalkyl,
4.(C
6-C
12) aryl-(C
1-C
6) alkyl, benzyl preferably,
5. phenyl, or
6.(C
1-C
9) heteroaryl,
R(19) be 1. hydrogen,
2.(C
1-C
6) alkyl,
3.(C
3-C
8) cycloalkyl,
4. phenyl, or
5. benzyl;
R(20) be 1. hydrogen,
2.(C
1-C
6) alkyl,
3.(C
3-C
8) cycloalkyl,
4. phenyl-(CH
2) q-,
5.OR（19），
6.NR(25) R(26), or
7.
R(21) be cyano group, nitro or CO
2R(18);
R(22) be CO
2R(6) or CH
2CO
2R(6);
R(23) be hydrogen, halogen, (C
1-C
4) alkyl or (C
1-C
4) alkoxyl group;
R(24) be hydrogen, (C
1-C
4) alkyl or phenyl;
R(25) and R(26) be identical or different, can be
1. hydrogen,
2.(C
1-C
4) alkyl,
3. phenyl,
4. benzyl, or
5. α-Jia Jibianji;
D is NR(23), O or CH
2;
B is O, NR(18) or S;
T is 1. singly-bounds,
2.-CO-，
3.-CH
2-，
4.-O-，
5.-S-，
6.-NR（28）-，
7.-CO-NR（28）-，
8.-NR（28）-CO-，
9.-O-CH
2-，
10.-CH
2-O-，
11.-S-CH
2-，
12.-CH
2-S-，
13.-NH-CR（27）R（29）-，
14.-NR（28）-SO
2-，
15.-SO
2-NR（28）-，
16.-CR（27）R（29）-NH-，
17.-CH＝CH-，
18.-CF＝CF-，
19.-CH＝CF-，
20.-CF-CH-，
21.-CH
2-CH
2-，
22.-CF
2-CF
2-，
23.-CH（OR）（6））-，
24.-CH（OCOR（19））-，
25.
26.
27) being identical or different and R(29), can be hydrogen, (C
1-C
5) alkyl, phenyl, allyl group or benzyl;
R(28) be hydrogen, (C
1-C
6) alkyl, benzyl or allyl group;
R(30) be 1.NR(27) R(28),
2. urea groups,
3. thioureido,
4. toluene-4-alkylsulfonyl, or
5. phenylsulfonamido;
R(31) and R(32) can be identical or different, can be (C
1-C
4) alkyl, perhaps R(31) and R(32) be together-(CH
2) q-;
Q is CH
2, NH, O or S;
N is integer 1-5;
M is integer 0-3;
O is integer 1-10;
R is zero, 1 or 2,
Alkyl, alkenyl and alkynyl can be straight or brancheds.Same situation is applicable to by its deutero-group, as alkanoyl or alkoxyl group.
Cycloalkyl also is understood to mean the ring that alkyl replaces.
(C
6-C
12) aryl for example has phenyl, naphthyl or xenyl, preferably phenyl.Same situation is applicable to by its deutero-group, as aroyl or aralkyl.
(C
1-C
9) heteroaryl especially is understood to mean by phenyl or naphthyl deutero-group, wherein 1 or 1 above CH group are replaced by N, and/or wherein at least 2 adjacent CH groups are replaced (forming five yuan of aromatic rings simultaneously) by S, NH or O.In addition, to condense 1 of position (as in the indolizine base) or 2 atoms also can be nitrogen-atoms to bicyclic radicals.
Above-mentioned group has for example furyl, thienyl, pyrryl, imidazolyl, pyrazolyl, triazolyl, tetrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidyl, pyrrole diazine, indyl, indazolyl, quinolyl, isoquinolyl, 2 base, quinoxalinyl, quinazolyl, cinnolines base.
The assorted dicyclo AH(of condensed therefrom derives group A) especially be understood that to mean the bicyclic system of 8-10 annular atoms (wherein maximum 9 annular atomses are carbon atom), wherein 2 adjacent atoms constitute 2 rings together.By benzenesulfonamide derivative, wherein 1 or 1 above CH group are by N, O on 1 or 2 the described loop types
+And S
+Replace, and/or wherein 2 adjacent CH groups are by S, NH or O replace (forming five yuan of aromatic rings simultaneously).
For example A can be the group of following compound: thionaphthene, cumarone, indoles, isoindole, indazole, benzoglyoxaline, quinoline, isoquinoline 99.9,2,3-naphthyridine, quinoxaline, quinazoline, cinnolines, benzothiazole, benzothiazole-1,1-dioxide, tonka bean camphor, chroman, benzoxazoles, benzisothiazole, benzodiazine, benzotriazole, phentriazine, benzoxazine, imidazopyridine, imidazopyrimidine, Imidazopyrazines, Imidazopyridazine, Imidazothiazole, Pyrazolopyridine, thienopyridine and pyrrolopyrimidine.Above-mentioned assorted dicyclo AH can also be hydrogenated partially or completely.It is better that but 1 ring of AH remains aromatic ring, and benzo-fused assorted dicyclo AH is good especially.
Under the situation that contains S and/or fractional saturation group, dicyclo also can be that for example oxygen replaces, (usually at phendioxin, 2, such in the 3-triazinone group).
Carry out the bonding of A by isocyclic part or heterocyclic moiety, if q is zero, by alkane 2 basis bridge L; If q=1 by singly-bound, obtains
Carbocyclic ring or heterocycle XH
2(therefrom deriving list or bicyclic group X) is understood that to mean the group of following compounds, for example pentamethylene, hexanaphthene, suberane, cyclopentenes, tetrahydrobenzene, suberene, benzene, naphthalene, furans, thiophene, pyrroles, pyridine, pyridazine, pyrimidine, piperidines, piperazine, morpholine, indoles, indazole, oxazole, isoxzzole, quinoline, isoquinoline 99.9, thionaphthene, cumarone, benzothiazole, benzoxazoles, imidazopyridine, imidazopyrimidine and furo pyridine.
Halogen is meant fluorine, chlorine, bromine or iodine.
The salt that can tolerate on the physiology of formula I compound is understood that its organic salt and inorganic salt, as at the Pharmaceutical of Remington Sciences, the 17th edition, p1418(1985) described in.Stability and solubleness according to physics and chemistry, acidic-group is meant sodium, potassium, calcium and ammonium salt especially preferably, basic group is meant and hydrochloric acid, sulfuric acid, phosphoric acid, carboxylic acid or sulfonic acid preferably, as the salt of acetate, citric acid, phenylformic acid, toxilic acid, fumaric acid, tartrate and tosic acid generation.
Compound is the salt that can tolerate on formula II compound and the physiology thereof preferably.
Each symbol has following meaning in the formula:
Z(1), Z(3 Z(2)) and Z(4) be
1.-CH
2-，
2.-CH＝，
3. the group of definition in 2, wherein 1 or 2 methyne groups are replaced by nitrogen, Z(4)=N is better,
R(1) be 1.(C
1-C
10) alkyl,
2.(C
3-C
10) alkenyl,
3.(C
3-C
10) alkynyl,
4.(C
3-C
8) cycloalkyl,
5. benzyl, perhaps.
6. the benzyl that replaces as previously discussed;
R(2) and R(3) be identical or different, can be
1. hydrogen,
2. hydroxyl
3. halogen
4. do not replace or by identical or different halogen, the hydroxyl, (C of being selected from more than 1 or 1
1-C
4) alkoxyl group, (C
1-C
4) straight or branched (C that replaces of alkylthio and sulfydryl substituting group
1-C
4) alkyl;
5.-CO
2R（6）;
T be singly-bound ,-O-,-CO-,-NHCO-or-OCH
2-, above definition is seen in other groups and variation thereof.
Good especially formula II compound is the salt that can tolerate on following formula: compound and the physiology thereof, R(1 in the formula) be (C
1-C
7) alkyl, (C
3-C
7) alkenyl or (C
3-C
7) alkynyl;
R(6) be hydrogen or (C
1-C
4) alkyl;
R(12) and R(13) being identical or different, can be hydrogen or (C
1-C
4) alkyl;
R(14) be 1.(C
1-C
4) alkyl,
2.(C
1-C
4) alkoxyl group,
3. cyano group,
4. amino,
5. nitro,
6. fluorine, chlorine or bromine,
7.(C
1-C
4) heteroaryl-CH
2,
8.(C
1-C
4) alkanoyloxy,
9.(C
1-C
4) alkanoyl
Benzoyl or
11. tetrazyl;
R(15) be 1.(C
1-C
4) alkyl
2.(C
6-C
12) aryl
3.(C
1-C
3) alkanoyloxy
4.(C
1-C
4) alkoxyl group
5.(C
1-C
9) heteroaryl, 5-tetrazyl preferably,
6. cyano group,
7. nitro,
8. hydroxyl,
9.SO
3R（6），
10. chlorine, bromine,
11.CO
2R（6），
12.CO-NH-R（19），
13.CO-R（20），
14.SO
2-NR（18）-CO-NR（17）R（16），
15.SO
2Or SO NR(18)-CO-O-R(17)
2N(CO-OR(17))
2,
16.CO-CHR（19）-CO
2H，
17.(C
1-C
4) alkyl-CO
2H,
18.NH-CO-NH-SO
2-CH
2-R（19），
22.
Or
23.R(14) with R(15) formation-CO-NH-SO
2;
L is-CH
2-;
R(18) be hydrogen;
R(25) and R(26) be hydrogen or (C independently of each other
1-C
4) alkyl.
The invention still further relates to the method for preparation; this method comprises carries out alkylation with formula III compound with formula IV compound, in addition, at random sloughs the protecting group of interim introducing; and at random the formula I compound that obtains is transformed into the salt that can tolerate on its physiology
R(1 wherein), R(2), R(3), R(4), R(5) and the definition of X the same,
L, q, R(12 in the formula), R(13) and the definition of A the same, U is a leavings group.
The preferably nucleofugic group of suitable leavings group U (referring to Angew, Chem.72(1960)) is as halogen, neighbour-tosylate, mesylate or fluoroform sulphonate.
The method of preparation formula III precursor is open, particularly at United States Patent (USP) 4,880.804, German Patent 3,911,603, european patent application 399,731,399732,400,835,400,974,415,886, existing narration in 420,237,425,921 and 434,038.
For the alkylation of formula III compound, for example suitable benzyl halide, tosylate, mesylate or fluoroform sulphonate or suitable alkylogen, tosylate, mesylate or fluoroform sulphonate are suitable for.
Above-claimed cpd can for example make corresponding methyl precursor carry out halogenation by known method preparation itself.Use N-bromine succinimide for this reason and be advisable, referring to for example J.Org.44,4733(1979) with Helv.Chim.Acta 62,2661(1979).
On ring, have CH
3The existing report of the synthetic method of the benzoglyoxaline of group, thionaphthene, imidazopyridine and imidazopyrimidine derivative, particularly in following document: R.P.Dickson etc., J.Med.Chem.29,1637(1986), E.Abignente etc., J.Heterocyclic Chem.26,1875(1989), A.Koubsack etc., J.Org.Chem.41,3399(1976) and F.Santer etc., Mh.Chem.99,715(1968).
Be starting raw material for example,,, can synthesize biphenyl derivatives by carrying out coupling with the aryl halide that replaces with transition-metal catalyst (particularly palladium) with the aryl boric acid derivative.R.B.Miller etc. is seen in suitable reaction, and Organometallics 1984,3,1261 or A.Zuzuki etc., and Synthetic Commun.11(7), 513(1981).
In inert solvent; in boiling temperature up to suitable solvent; by the suitable sulphonamide of formula I by reacting with chlorinated carbonates; perhaps, can obtain the alkylsulfonyl urethane derivatives of formula I by reacting with dimethyl carbonic acid hydrogen ester (dimethyl dicarbonate) and alkali (as salt of wormwood)
In high boiling inert solvent (as DMSO); from the suitable sulphonamide of formula I by with isocyanate reaction or with 2 of suitable amine; 2; 2-trichloroacetamide derivatives reaction; perhaps in high boiling inert solvent (as toluene); from the effect of the alkylsulfonyl urethane of formula I by suitable amine, can make the sulphonyl urethane derivatives of formula I, reaction is to carry out under the boiling temperature of each solvent.
If desired, can with the aminocompound starting raw material, reset the preparation sulfamide compound by Meerwein.For this reason, at first the hydrochloride with this amine carries out diazotization, reacts with sulfurous gas in the presence of copper catalyst in glacial acetic acid then.Then the effect of ammonia causes generating sulfonamido.
By similar mode, carry out alkylation with known method substantially.
Formula III imidazoles condensed derivative is for example being metallized in the presence of the alkali.Alkali is the metal hydride of formula MH preferably, as lithium hydride, sodium hydride or potassium hydride KH, and with for example DMF or DMSO as solvent, perhaps alkali is the metal alkoxide of formula MOR, here R is methyl, ethyl or the tertiary butyl, and described metallization reaction is carried out in suitable alcohol, DMF or DMSO.The salt of this imidazolo derivatives of so generating is dissolved in the aprotonic solvent (as DMF or DMSO), and handles with the alkylating agent of appropriate amount.
The other method of imdazole derivatives deprotonation is for example to react with salt of wormwood in DMF or DMSO.
Be reflected at and be lower than the boiling temperature of room temperature one, be preferably under the boiling temperature of 20 ℃-reaction mixture about 1-10 hour until reaction mixture.
Formula I compound of the present invention has antagonistic action to angiotensin-ii-receptor, therefore can be used for treating the hypertension relevant with angiotensin.Cardiovascular disorder such as the moment local asphyxia outbreak and the big cerebral apoplexy that also might be used in addition, cardiac insufficiency, Cardioprotective, myocardial infarction, megalocardia, arteriosclerosis, ephrosis, renal failure and brain.
Renin is a kind of proteolytic ferment in the aspartyl protease class, and it is to be secreted under multiple stimulation (sodium, beta-receptor stimulation are exhausted, hanged down to Q volume of blood) effect by the juxtaglomerular cell of kidney to enter circulation of blood.In circulation of blood, renin makes the proangiotensin by hepatic secretion be cracked into the decapeptide angiotensin.The latter further changes into angiotensin by Zinc metallopeptidase Zace1 (ACE) catalysis.Angiotensin plays an important role aspect regulating blood pressure, because it can directly make blood pressure increase by vasoconstriction.In addition, it can also stimulate the acth secretion aldosterone, and by this way, by suppressing the sodium secretion, increases the extracellular liquid volume, and this itself helps to increase blood pressure equally.
Back receptor effect especially comprises stimulates phosphoinositide to transform (Ca
2+Discharge), the hormone receptor that PKC is relevant with AMP with utilization.
Compound can be by measuring to the avidity of angiotensin-ii-receptor in the formula I
125I-angiotensin or
3The H-angiotensin is detected from the metathesis on the glomerular zone membrane receptor of bovine adrenal.In order to carry out this detection, prepared glomerular zone film is suspended in the damping fluid of PH7.4.For preventing the degraded of radioligand between incubation period, add anti-albumen phthalein enzyme-peptidase inhibitors.Add single-minded activity in addition and be the 74TBq/ mmole 14000cpm tracer element (available from Amersham Buchler company) and can be in conjunction with the receptor protein of 50% tracer element.In the mixture that 100ul damping fluid+protease inhibitor (containing or do not contain the 50ul damping fluid and the 50ul tracer element of angiotensin or receptor antagonist) is formed, add 50ul film suspension, to start reaction.25 ℃ of incubations are after 60 minutes,
On the cell harvesting instrument, use Whatmann
The GFIC strainer is separated bonded and free radioligand with filtration method.
(Sigma company, No.3143) solution (PH10) processing filters is so that prevent non-specific binding, by measuring the radioactivity on the gamma scintillation counter, the displacement intensity of radioligand on the evaluation acceptor with 0.3% polymine.Method (J.Theor.Biol.59,253(1970)) according to Chem. etc. calculates IC
50The value value is promptly replaced the required inhibitor concentration of 50% part.Concerning the formula I compound, its IC
50The value scope is 1 * 10
-4-1 * 10
-9M.
On the other hand, formula I compound can be by measuring to the avidity of angiotensin-ii-receptor
125The angiotensin of I mark or
3The acceptor of the angiotensin displacement Different Organs (liver, lung, suprarenal gland, brain etc.) of H mark is evaluated.
According to this purpose, prepared film is suspended in incubation buffering liquid, and (20mM Tris, PH7.4 contain 135mM NaCl, 10mM KCl, 10mM MgCl
2, 5mM glucose, 0.2% bovine serum albumin 0.3mM proteinase inhibitor PMSF and 0.1mM bacitracin) in, the test-compound with nervous plain II of the label vascular with radioactivity and different concns placed 25 ℃ of incubations 90 minutes.Then on cell harvesting instrument (SKATRON), by micro glass fabric filter (GF51, Schleicher ﹠amp; Schull company) filters, bonded and free radioligand are separated.
By measure on the strainer radioactivity with receptors bind with beta spectrometer or gamma spectrometer, evaluation is by the ability of test compound from acceptor displacement radioligand.Radioligand from the acceptor the metathetical ability with IC
50Value representation is promptly from the needed inhibitor concentration of acceptor displacement 50% binding partner.(LIGAND, G.A.Mcpherson 1985, Elsevier-BIOSOFT, 68 Hills Road, Cambridge CB 21LA, UK) calculating IC with PC software
50Value.The IC of measured formula I compound
50The scope of value is 1 * 10
-5～1 * 10
-11M.
In order to measure formula I compound antagonistic action in vivo, at the Sprague-Dawley rat (M that emedullates
Llegard Denmark) measures the restraining effect that blood pressure that these compounds cause angiotensin increases on the model.In carotid artery, measure blood pressure, vein (penile vein) drug administration by injection.Prepare animal and through probationary period of 20 minutes with after stablizing every hemodynamic parameter, quiet notes concentration is 10 nanogram(ng)s/0.1ml; Continuous 3 times of the angiotensin aqueous solution of 30 nanogram(ng)s/0.1ml and 100 nanogram(ng)s/0.1ml, each 5 minutes at interval.The formula I compound is dissolved in the distilled water, and if desired, other adds 10% ethanol and (or) alkali (PH＜10) (or) acid (PH＞3), and quiet injecting amount is that 1-300 microgram/kilogram or intramedullary injection dosage are 5-1000 microgram/kilogram.Under the situation of intramedullary injection, after 20,40 and 60 minutes, inject angiotensin respectively, and under the intravenous injection situation, carried out the compressive reaction sequencing every 10 minutes.
The formula I compound is effectively through intravenously administrable, and particularly dosage also is that effectively particularly dosage is in the scope of 5-300 microgram/kg body weight through duodenal administration in the scope of 1-300 microgram/kg body weight.
The invention still further relates to the medicinal compositions of forming by active compound such as diuretic(s) or non-steroidal anti-inflammatory activity compound by formula I compound and other.The formula I compound can also be as the diagnostic reagent of vasotonia protoenzyme-hypertensin system.
Medicinal preparations contains formula I active compound and other active compounds of acceptable and the inorganic or organic pharmaceutical excipient of significant quantity.Can intranasal administration, intravenous administration, subcutaneous administration or oral administration administration.The dosage of active compound is decided with kind, body weight, age and the administering mode of warm-blooded animal.
Method with known dissolving own, mixing, granulation or dressing prepares medicinal preparations of the present invention.
For the oral administration form, active compound is mixed with the additive that is generally used for this purpose such as vehicle, stablizer or inert diluent, and produce the suitable form of taking such as tablet, coated tablet, hard-gelatin capsules, water suspension, pure suspensoid or oil suspension or aqueous pharmaceutical, alcoholic solution agent or oily solution by usual method.The inert support that can use has for example gum arabic, magnesium oxide, magnesiumcarbonate, potassiumphosphate, lactose, glucose, fumaric acid octadecyl ester magnesium or starch, particularly W-Gum.Preparation can be dried particle in this case, or wet granular.Suitable oily vehicle or solvent have for example vegetables oil or animal oil, as sunflower oil and haddock liver oil.
For subcutaneous administration or intravenously administrable, if desired,, make solution, suspensoid or emulsion together as solubility promoter, emulsifying agent or other auxiliarys with salt that can tolerate on active compound or their physiology and the material of using always for this purpose.The available solvent has for example water, normal saline solution or alcohol (as ethanol, propylene glycol or glycerol), also has the sugar soln (as glucose or mannitol solution) or the mixed solution of above-mentioned all kinds of SOLVENTS in addition.
According to the method described above, for example measured the following IC of embodiment 1,2,3,15,19,27,31 and 51 compounds
50Value:
Example I C
50(nM)
1 78
2 65
3 149
15 0.8
19 0.74
27 1.1
31 0.48
51 1.8
The abbreviation table:
DCI: desorb-chemi-ionization
DMF:N, dinethylformamide
EA: ethyl acetate
FAB: fast atom bombardment
H: hour
Hep: normal heptane
Min: minute
NBS:N-bromine succinimide
RT: room temperature
Embodiment 1
2-normal-butyl-1-((2-carboxyl-3-chlorobenzene is (b) thiophene-6-yl also) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 2-carboxyl-6-nitrobenzamide
30 gram (0.155 mole) 3-nitrophthalic acid acid anhydride gradation are added in the 180ml strong aqua, and the solution of generation is under agitation in 100 ℃ of heating 45 minutes.Mixture in rotary evaporator, evaporate and with toluene condistillation 2 times, resistates is dry under high vacuum.With it with the EA(ethyl acetate) stir, cream-coloured precipitation leaches through suction filtration, under vacuum through P
2O
5Dry.Obtain 31.8 gram title compounds.
Fusing point: 188 ℃
Rf（SiO
2，CH
2Cl
2/MeOH 1∶1）＝0.3
MS（DCI）：211（M+H）
B) 2-amino-3-nitrobenzoic acid
With 31 gram (0.147 mole) embodiment 1a) compound is dissolved in the 50m14N sodium hydroxide solution, adds 100ml water and 150ml chlorine bleach liquor (being excessive with the potassium iodide starch test paper test), and the solution of gained was in 100 ℃ of heating 60 minutes.After reaction is finished with its cooling, and with the saturated Na of 250ml
2CO
3The saturated KH of solution and 400ml
2PO
4Solution-treated is adjusted to 3 with the dense HCl of 4N Hcl/ with the PH of solution, and product is with EA extraction 3 times, each 500ml.Through MgSO
4After the drying, concentrate, and stir, obtain 18 gram title compounds with Di Iso Propyl Ether.
Fusing point: 188-194 ℃
Rf（SiO
2，CH
2Cl
2/MeOH 1∶1）＝0.7
MS（DCI）：183（M+H）
C) 2-amino-3-nitrobenzoic acid methyl esters
With 18 gram (99 mmole) embodiment 1b) compound and 200ml methyl alcohol, 20ml thionyl chloride stirred 48 hours under refluxing together.Reaction soln evaporates in rotary evaporator, and resistates is dissolved in the saturated Na of 400ml
2CO
3In the solution, this solution extracts 3 times with EA, the rare Na of the organic phase of merging
2CO
3Solution and saturated NaCl solution washing are through Na
2SO
4Drying, and concentrate.Pass through SiO
2Chromatography is used the EA/Hep(ethyl acetate/heptane) 9: 1 and 7: 3 wash-outs, obtain 11.5 gram title compounds.
Fusing point: 86-88 ℃
Rf（SiO
2，EA/Hep 1∶1）＝0.5
MS（DCI）：197（M+H）
D) 2-(the positive pentanoyl of N-() amino)-3-nitrobenzoic acid methyl esters
7 gram (35.5 mmole) embodiment 1c) compound and 50ml valeryl chloride one arise from 110 ℃ of stirrings 1 hour.Mixture is concentrated into dried, resistates with activated carbon treatment 30 minutes, and filters in ether, and concentrated filtrate, resistates are through the SiO chromatography purification, with 2: 8 wash-outs of EA/Hep.Obtain 5.8 gram title compounds.
Fusing point: 66-69 ℃
Rf（SiO，EA/Hep 1∶1）＝0.4
MS（DCI）：281（M+H）
E) 6-brooethyl-3-chloro-2-methoxycarbonyl benzo (b) thiophene
2.5 gram (10.4 mmole) 3-chloro-2-methoxycarbonyl-6-methyl benzo (b) thiophene (press J.Org.Chem.41,3399(1976) described method preparation) were restrained NBS and 420 milligrams of dibenzoyl peroxide reflux 5 hours with 150ml chlorobenzene, 1.87.Steam except that behind the chlorobenzene in rotary evaporator, the resistates that obtains is dissolved among the EA, EA solution is used saturated NaHCO solution, 10%Na successively
2SO
3Solution and saturated NaCl solution washing are through Na
2SO
4Drying, and concentrate.Pass through SiO
2Chromatography with 1: 20 wash-out of EA/Hep, obtains 2.28 gram title compounds.
Fusing point: 143-145 ℃
Rf（SiO
2，EA/Hep 1∶20）＝0.3
MS（DCI）：319，321（M+H）
F) amino-3-nitrobenzoic acid methyl esters 2-(the positive pentanoyl of N-()-((3-chloro-2-methoxycarbonyl benzo (b) thiophene-6-yl) methyl))
With 800 milligrams of (2.86 mmole) embodiment 1 d) compound is dissolved in the 5ml dry DMF, and solution is with 395 milligrams of K
2CO
3Handle, mixture stirred under room temperature 10 minutes.To wherein dripping 913 milligrams of embodiment 1 e) solution of compound in the 20ml dry DMF.Reaction soln stirs under room temperature and spends the night.Steam under vacuum and remove DMF, resistates is dissolved among the EA, EA uses H mutually successively
2O, rare NaHCO
3Solution, saturated NaHCO
3Solution and saturated NaCl solution washing are through Na
2SO
4Dry and concentrated.Pass through SiO
2Chromatography with 1: 2 wash-out of EA/Hep, obtains 860 milligrams of title compounds.
Rf（SiO
2，EA/Hep 1∶2）＝0.3
MS（FAB）：519（M+H）
G) 2-normal-butyl-1-((3-chloro-2-methoxycarbonyl benzo (b) thiophene-6-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
With 450 milligrams of (0.85 mmole) embodiment 1f) compound places 50ml ethanol, and hydrogenation is 1 hour in the presence of Raney nickel.Filtration catalizer, concentrated filtrate is to doing, and gained resistates and 10ml EA/ Virahol (1: 1) and the saturated EA solution one of 10mlHCl-arise from 50 ℃ and stirred 30 minutes.Concentrate the back and use methanol crystallization, obtain 190 milligrams of title compounds.
Fusing point: 167-170 ℃ (decomposition)
Rf（SiO
2，CH
2Cl
2/MeOH/NH
4OH 49/1/0.1）＝0.3
MS（DCI）：471（M+H）
H) 2-normal-butyl-1-((2-carboxyl-3-chloro benzo (b) thiophene-6-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
With 185 milligrams of (0.39 mmole) embodiment 1g) compound is dissolved in the 10ml ethanol, adds 1ml H
2O and 1ml concentrated NaOH solution, the solution of gained was in stirring at room 3 hours.Steam under vacuum and remove EtOH, the aqueous solution transfers to PH3, the precipitation that suction filtration is separated out with the acid of ice ester.Under high vacuum, after the drying, obtain 100 milligrams of title compounds, be white crystal.
Fusing point:＞260 ℃
Rf（SiO
2，EA/MeOH 2/1）＝0.18
MS（FAB）：443（M+H）
Embodiment 2
2-normal-butyl-1-((3-carboxyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 2-benzoyl-2-ethyl bromoacetate
With the 25ml(0.144 mole) ethyl benzoylacetate is dissolved in 50mlCCl
4In, dripping the 8.5ml bromines in 5 ℃, this brown solution stirred 1 hour in 5 ℃ successively, in stirring at room 3 hours, and stirred 2 hours in 60 ℃.It is concentrated into dried, resistates is dissolved among the EA, and EA solution is used 10%Na successively
2SO
3Solution and saturated NaCl solution washing are through MgSO
4Dry and concentrated, resistates is dry under high vacuum.Obtain 38 gram title compounds, be red oil.
Rf（SiO
2，EA/Hep 1/6）＝0.28
MS（DCI）：271，273（M+H）
B) 7-methyl-2-phenylimidazole (1,2-a) pyridine-3-carboxylic acid ethyl ester also
With 38 gram (0.14 mole) embodiment 2 a) compound and 15.2 gram 2-amino-4-picolines place ethanol, and under refluxing, stirred 8 hours.Mixture is concentrated into dried, the saturated Na of resistates
2CO
3Solution-treated is used the EA extracted several times, and the organic phase of merging is with saturated NaCl solution washing, through Na
2SO
4Drying, and concentrate.Pass through SiO
2Chromatography with 2: 1 wash-outs of EA/Hep, obtains 12.2 gram title compounds.
Rf（SiO
2，EA/Hep 2∶1）＝0.3
MS（DCI）：281（M+H）
C) 7-brooethyl-2-phenylimidazole (1,2-a) pyridine-3-carboxylic acid ethyl ester also
Restrain (10.7 mmole) embodiment 2 b with 1.27 gram NBS and 150 milligrams of benzoyl peroxides with 3) the described method preparation of compound bromination (pressing embodiment 1e)).Obtain 1.2 gram title compounds.
Rf（SiO
2，EA/Hep 1/2）＝0.2
MS（DCI）：359，361（M+H）
D) amino-3-nitrobenzoic acid methyl esters 2-(the positive pentanoyl of N-()-(3-ethoxy carbonyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)
With 800 milligrams of (2.85 mmole) embodiment 1d) compound, 1.03 gram embodiment 2c) compound and 400 milligrams of K
2CO
3By embodiment 1f) described method reacts.Obtain 520 milligrams of title compounds.
Rf（SiO
2，EA/Hep 1∶1）＝0.2
MS（FAB）：559（M+H）
E) 2-normal-butyl-1-((3-ethoxy carbonyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
With 400 milligrams of (0.71 mmole) embodiment 2d) compound is by embodiment 1g) described method reacts.From methyl alcohol, separate out post precipitation with ether, obtain 250 milligrams of title compounds.
Fusing point: 217-220 ℃ (decomposition)
Rf（SiO
2，EA/Hep 9/1）＝0.5
MS（DCI）：511（M+H）
F) 2-normal-butyl-1-((3-carboxyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-1H-benzoglyoxaline-7-carboxylic acid
With 230 milligrams of (0.45 mmole) embodiment 2 e) compound is by embodiment 1h) described method is hydrolyzed.Obtain 117 milligrams of title compounds, be white crystal.
Fusing point: 202-204 ℃
Rf（SiO
2，EA/MeOH 2∶1）＝0.1
MS（FAB）：469（M+H）
Embodiment 3
2-normal-butyl-1-((3-carboxyl-2-phenylimidazole is (1,2-a) pyrimidin-7-yl also) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 7-methyl-2-phenylimidazole (1,2-a) pyrimidine-3-carboxylic acid, ethyl ester also
Use embodiment 2a) compound and 2-amino-4-methylpyrimidine, by example 2b) described method prepares title compound.
Rf（SiO
2，EA/Hep 2∶1）＝0.2
MS（DCI）：282（M+H）
B) 7-brooethyl-2-phenylimidazole (1,2-a) pyrimidine-3-carboxylic acid, ethyl ester also
With 2 gram (7.11 mmole) embodiment 3a) compound, press embodiment 2c) described method preparation, obtain 510 milligrams of title compounds.
Rf（SiO
2，EA/Hep 1∶2）＝0.2
MS（FAB）：360，362（M+H）
C) 2-(the positive pentanoyl of N-()-(3-ethoxy carbonyl-2-phenylimidazole is (1,2-a) pyrimidin-7-yl also) methyl)-amino-3-nitrobenzoic acid methyl esters
With 435 milligrams of (1.55 mmole) embodiment 1d) compound and 558 milligrams of embodiment 3b) compound, press embodiment 1f) described method preparation, obtain 550 milligrams of title compounds.
Rf（SiO
2，EA/Hep 2∶1）＝0.2
MS（DCI）：560（M+H）
D) 2-normal-butyl-1-((3-ethoxy carbonyl-2-phenylimidazole is (1,2-a) pyrimidin-7-yl also) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
With 380 milligrams of (0.68 mmole) embodiment 3c) compound, press embodiment 1g) described method preparation, and obtain 102 milligrams of title compounds, be light cream-coloured crystal mass.
Fusing point: 185-187 ℃
Rf（SiO
2，EA/Hep 1∶1）＝0.2
Ms（FAB）：512（M+H）
E) 2-normal-butyl-1-((3-carboxyl-2-phenylimidazole is (1,2-a) pyrimidin-7-yl also) methyl)-1H-benzoglyoxaline-7-carboxylic acid
With 45 milligrams of (0.09 mmole) embodiment 3d) compound, press embodiment 1h) described method preparation, obtain 31 milligrams of title compounds.
Fusing point:＞260 ℃
Rf（SiO
2，EA/MeOH）＝0.1
Ms（FAB）：470（M+H）
Embodiment 4
2-normal-butyl-3-((2-carboxyl-3-chloro benzo (b) thiophene-6-yl) methyl)-3H-imidazo (4,5-b) pyridine
A) 2-normal-butyl-3H-imidazo (4,5-b) pyridine
10 gram (91.6 mmole) 2,3 diamino pyridines and 27.4 gram valeric acids were stirred 18 hours in 170 ℃.After reaction is finished, mixture 100mlCH
2Cl
2Saturated NaHCO is used in dilution successively
3Solution, water and saturated NaCl solution washing are through Na
2SO
4Dry and concentrated.Pass through SiO
2Chromatography, use EA/Hep20: 1 wash-out obtains 9.7 gram title compounds.
Fusing point: 103 ℃
Rf（SiO
2，EA/MeOH 20∶1）＝0.3
Ms（DCI）：176（M+H）
B) 2-normal-butyl-3-((3-chloro-2-methoxycarbonyl benzo (b) thiophene-6-yl) methyl)-3H-imidazo (4,5-b) pyridine
300 milligrams of (0.94 mmole) embodiment 1e) compound and 175 milligrams of embodiment 4a) compound and 552 milligrams of K
2CO
3, 10ml DMF one arised from stirring at room 8 hours.Mixture is concentrated into dried, resistates is dissolved among the EA, and EA solution is used H successively
2O, rare KHSO
4Solution, saturated NaHCO
3Solution and saturated NaCl solution washing are through Na
2SO
4Dry and concentrated.Pass through SiO
2Chromatography, use EA/Hep1: 1 wash-out, obtain 130 milligrams of title compounds, be pale yellow powder.
Fusing point: 127-129 ℃
Rf（SiO
2，EA/Hep 1∶1）＝0.2
MS（DCI）：414（M+H）
C) 2-normal-butyl-3-((2-carboxyl-3-chlorobenzene is (b) thiophene-6-yl also) methyl)-3H-imidazo (4,5-b) pyridine
With 117 milligrams of (0.28 mmole) embodiment 4b) compound, by embodiment 1h) described method reacts.Obtain 107 milligrams of title compounds, be white powder.
Fusing point:＞260 ℃
Rf（SiO
2，EA/MeOH 2∶1）＝0.3
MS（FAB）：400（M+H）
Embodiment 5
2-normal-butyl-3-((3-carboxyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
A) 2-normal-butyl-3-((3-ethoxy carbonyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 2c) and 4a) compound, by embodiment 4b) described method prepares title compound.
MS（DCI）：454（M+H）
B) 2-normal-butyl-3-((carboxyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 5a) compound, by embodiment 1h) described method prepares title compound.
MS（FAB）：426（M+H）
Embodiment 6
2-normal-butyl-3-((3-carboxyl-2-phenylimidazole is (1,2-a) pyrimidin-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
A) 2-normal-butyl-3-((3-ethoxy carbonyl-2-phenylimidazole is (1,2-a) pyrimidin-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 3b) and 4a) compound, by embodiment 4b) described method prepares compound.
MS（DCI）：455（M+H）
B) 2-normal-butyl-3-((3-carboxyl-2-phenylimidazole is (1,2-a) pyrimidin-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 6a) compound, press embodiment 1h) described prepared in reaction title compound.
MS（FAB）：427（M+H）
Embodiment 7
2-normal-butyl-3-(2-(4-aminomethyl phenyl)-3-(1H-tetrazolium-5-yl) imidazo (4,5-b) pyridyl)-3H-imidazo (4,5-b) pyridine
A) imidazo (4,5-a) pyridine 2-(4-aminomethyl phenyl)
With 8.6 gram (91.4 mmole) 2-aminopyridine and 7.7 gram (45.7 mmole) chloromethyl p-methylphenyl ketone (press Chem.Lett., 1990, the preparation of 1125-1128 method) in 130 ℃ of stirrings 45 minutes.Reaction soln CH then
2Cl
2Dilution, water and saturated NaCl solution washing successively are through MgSO
4Dry and concentrated.Pass through SiO
2Chromatography, use EA/Hep 4: 1-1: 1 wash-out obtains 6.8 gram title compounds.
Fusing point: 142-144 ℃
Rf（SiO，EA/Hep 1∶1）＝0.2
MS（DCI）：209（M+H）
B) imidazo (4,5-a) pyridine 3-formyl radical-2-(4-aminomethyl phenyl)
In 0 ℃ with the 21ml(0.27 mole) DMF 3.6ml POCl
3At 60ml CH
2Cl
2In solution-treated, reaction soln is in stirring at room 30 minutes, in 0 ℃ to wherein dripping 6.8 gram (32.7 mmole) embodiment 7a) solution of compound., after 2 hours mixture is concentrated in 60 ℃ of stirrings, resistates restrains NaOH at 200mlH with 20
2Solution-treated among the O, and under refluxing, stirred 1 hour, in ice bath, separate out precipitation after the cooling, and suction filtration goes out.Use ethyl alcohol recrystallization, obtain 5.5 gram title compounds.
Fusing point: 168-171 ℃
Rf（SiO
2，EA/Hep8∶2）＝0.4
MS（DCI）：237（M+H）
C) imidazo (4,5-a) pyridine 3-oximido-2-(4-aminomethyl phenyl)
2 gram (8.47 mmole) embodiment 7b) compound places 130ml methyl alcohol, and restrains the solution-treated of sodium acetates in 65ml water with 883 milligrams of oxammonium hydrochlorides and 1.04.Reaction soln stirred under room temperature 5 hours, stirred 1 hour under refluxing.Steam in rotary evaporator and remove methyl alcohol, residue diluted with water separate out precipitation after the cooling, and suction filtration goes out then.Under high vacuum through P
2O
5After the drying, obtain 2.04 gram title compounds.
Fusing point: 202-206 ℃
Rf（SiO
2，EA/Hep 1∶1）＝0.3
MS（DCI）：252（M+H）
D) imidazo (4,5-a) pyridine 3-cyano group-2-(4-aminomethyl phenyl)
Under ice-cooled and stirring, gradation adds 2.1 gram (9.0 mmole) embodiment 7c in the 45ml thionyl chloride) compound, reaction solution stirred under room temperature 45 minutes.With toluene thionyl chloride is steamed, carry out 2 times, resistates is dissolved among the EA, and EA solution is used saturated Na successively
2CO
3With saturated NaCl solution washing, through MgSO
4Dry and concentrated.With Di Iso Propyl Ether/EA recrystallization, obtain 1.9 gram title compounds.
Fusing point: 138-144 ℃
Rf（SiO
2，EA/Hep 1∶1）＝0.2
MS（DCI）：234（M+H）
E) 2-(3-2-bromomethylphenyl)-3-cyanogen imidazo (4,5-a) pyridine
With 1.7 gram embodiment 7d) compound, press embodiment 1e) described method preparation, obtain 1.73 gram title compounds.
Fusing point: 182-186 ℃
Rf（SiO
2，EA/Hep 1∶1）＝0.2
MS（DCI）：312/314（M+H）
F) 2-normal-butyl-3-(3-cyano group-2-(4-aminomethyl phenyl) imidazo (4,5-a) pyridyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 4a) and 7e) compound, by embodiment 4b) described method prepares title compound.
MS（DCI）：407（M+H）
G) imidazo (4,5-b) pyridyl 2-normal-butyl-3-(2-(4-aminomethyl phenyl)-3-(1H-tetrazolium-5-yl))-3H-imidazo (4,5-b) pyridine
With 210 milligrams of (0.51 mmole) embodiment 7f) compound places 5ml toluene, and stirred 3 days under refluxing with 308 milligrams of azide tin trimethyls.Reaction solution adds saturated KF solution of 7ml and 0.2ml HBF with the dilution of 4ml ether
4Stirred 2 days under room temperature solution (concentration is 50%) back.Mixture dilutes with EA, and filters, and tells the organic phase of filtrate, and water and saturated NaCl solution washing successively are through Na
2SO
4Drying, and concentrate.Pass through SiO
2Chromatography with 3: 1 wash-outs of EA/MeOH, obtains 110 milligrams of title compounds.
MS（FAB）：450（M+H）
Embodiment 8
2-normal-butyl-1-(2-(4-aminomethyl phenyl)-3-(1H-tetrazolium-5-yl) imidazo (4,5-a) pyridyl)-1H-benzoglyoxaline-7-carboxylic acid
A) amino-3-nitrobenzoic acid methyl esters 2-(the positive pentanoyl of N-()-(3-cyano group-2-(4-aminomethyl phenyl) imidazo (4,5-a) pyridyl).
Use embodiment 1d) and 7e) compound, by embodiment 1f) described method is prepared.In the method, with 730 milligrams of (2.34 mmole) embodiment 7e) compound and 655 milligrams of (2.34 mmole) embodiment 1d) compound, obtain 988 milligrams of title compounds.
Fusing point: 128-131 ℃
Rf（SiO
2，EA/Hep 8∶2）＝0.3
MS（DCI）：512（M+H）
B) 2-normal-butyl-1-(3-cyano group-2-(4-aminomethyl phenyl) imidazo (4,5-a) pyridyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Use embodiment 8a) compound, by embodiment 1g) described method prepares title compound.
Rf（SiO
2，CH
2Cl
2/MeOH 95∶5）＝0.2
Ms（DCI）：464（M+H）
C) imidazo (4,5-a) pyridyl 2-normal-butyl-1-(2-(4-aminomethyl phenyl)-3-(1H-tetrazolium-5-yl))-1H-benzoglyoxaline-7-carboxylate methyl ester
With 157 milligrams of (0.34 mmole) embodiment 8b) compound, by embodiment 7g) described method reacts, and obtains 88 milligrams of title compounds.
Fusing point: 120-155 ℃
Rf（SiO
2，CH
2Cl
2/MeOH 8∶2）＝0.3
Ms（FAB）：507（M+H）
D) 2-normal-butyl-1-(2-(4-aminomethyl phenyl)-3-(1H-tetrazolium-5-yl)-imidazo (4,5-a) pyridyl)-1H-benzoglyoxaline-7-carboxylic acid
Use embodiment 8b) compound, by embodiment 1h) described method prepares title compound.
Rf（SiO
2，CH
2Cl
2/MeOH/AcOH/H
2O 20∶15∶2∶4）＝0.8
Ms（FAB）：493（M+H）
Embodiment 9
5,7-dimethyl-2-ethyl-3-(2-carboxyl-3-chlorobenzene is (b) thiophene-6-yl also) methyl)-3H-imidazo (4,5-b) pyridine
A) 5,7-dimethyl-2-ethyl-3-((3-chloro-2-methoxycarbonyl benzo (b) thiophene-6-yl) methyl)-3H-imidazo (4,5-b) pyridine
With 500 milligrams of (2.8 mmoles) 5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine is (at european patent application 400, open in 974) place the 10ml dry DMF, under argon gas stream, be 50% with 165 milligrams of NaH(concentration) handle, after 30 minutes, in reaction soln, add 900 milligrams of (2.8 mmole) embodiment 4b) compound, mixture stirred under room temperature 2 hours.The reaction solution water treatment, and with EA extraction, the EA extraction liquid of merging is water and saturated NaCl solution washing successively, through MgSO
4Dry and concentrated.Pass through SiO
2Chromatography with 15: 1 wash-outs of EA/MeOH, obtains 700 milligrams of title compounds.
Rf（SiO
2，EA/MeOH 15∶1）＝0.3
MS（DCI）：414（M+H）
B) 5,7-dimethyl-2-ethyl-3-((2-carboxyl-3-chlorobenzene is (b) thiophene-6-yl also) methyl)-3H-imidazo (4,5-b) pyridine
With 680 milligrams of (1.64 mmole) embodiment 9a) compound, by embodiment 1h) described method reacts.Obtain 570 milligrams of title compounds.
MS（DCI）：400（M+H）
Embodiment 10
5,7-dimethyl-2-ethyl-3-((3-carboxyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
A) 5,7-dimethyl-2-ethyl-3-((3-ethoxy carbonyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
With 5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine (pressing the preparation of european patent application 400,974 methods) and 280 milligrams of (0.78 mmole) embodiment 2c) compound, press embodiment 9a) similarly method preparation, obtain 160 milligrams of title compounds.
Rf（SiO
2，EA）＝0.2
MS（FAB）：454（M+H）
B) 5,7-dimethyl-2-ethyl-3-((3-carboxyl-2-phenylimidazole is (1,2-a) pyridine-7-yl also) methyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 10b) compound, by embodiment 1h) described method prepares title compound.
MS（FAB）：426（M+H）
Embodiment 11
5,7-dimethyl-2-ethyl-3-((2-(4-aminomethyl phenyl)-3-(1H-tetrazolium-5-yl) imidazo (4,5-a) pyridyl)-3H-imidazo (4,5) pyridine a) 5,7-dimethyl-2-ethyl-3-(3-cyano group-2-(4-aminomethyl phenyl) imidazo (4,5-a) pyridyl)-3H-imidazo (4,5) pyridine
With 5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine (pressing european patent application 400,974 described method preparations) and embodiment 7e) the compound title compound.
MS（DCI）：407（M+H）
B) 5,7-dimethyl-2-ethyl-3-((2-(4-aminomethyl phenyl)-3-(1H-tetrazolium-5-yl) imidazo (4,5-a) pyridyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 11a) compound, by embodiment 7g) described method prepares title compound.
MS（FAB）：450（M+H）
Embodiment 12
3-((2 '-the amino-ethyl phenyl) carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine
A) sulfonamido bromobenzene
Under argon atmospher, in dense HCl of 100ml and 30ml glacial acetic acid solution, add 51.6 gram (0.3 mole) neighbour-bromanilines, drip 22.4 in-10 ℃ and restrain the solution of Sodium Nitrites in 30ml water, reaction solution stirred 60 minutes in-5 ℃.The drips of solution of gained is added to uses SO
27 saturated gram CuCl
22H
2In the 300ml glacial acetic acid solution of O and 0.5 gram CuCl., after 60 minutes mixture is poured in ice/water mixture in stirring at room, and used the saturated NaHCO of extracted with diethyl ether, ether extraction liquid
3Solution and water washing are through MgSO
4Dry and concentrated.The 67.8 gram sulfonyl chloride compounds that obtain place 500ml acetone, and handle with the 300ml strong aqua under cooling.Steam and remove acetone, the suspension dilute with water that obtains, the white crystal that suction filtration is separated out washes with water, and dry under high vacuum.This title compound need not to be further purified and promptly can be used for next step reaction.B) 2, N, N-dimethylamino formyl sulfonamido bromobenzene
With 0.236 mole of embodiment 12a) compound and 40mlN, the dinethylformamide dimethyl acetal places the 150ml dry DMF, and stirs 2 hours under room temperature.Pour reaction solution into 200ml 5%NaHSO
4In the solution/ice (1: 1), the precipitation that suction filtration is separated out washes with water, and dry under vacuum.Obtain 67 gram title compounds.
Rf（SiO
2，EA/Hep 1∶1）＝0.1
MS（DCI）：291/293（M+H）
C) 4 '-methyl diphenyl-2-N, N-dimethylamino formyl radical sulphonamide
Under argon gas stream, to 11 the gram (37.9 mmole) embodiment 12b) compound, 1 the gram triphenyl phosphine and 8 the gram Na
2CO
3150ml toluene and 40mlH
2In the solution of O, at first add 420 milligrams of Pd(OAc)
2, add subsequently 5.66 the gram (41.9 mmole) tolyl boric acid the 100ml ethanolic soln.With mixture ebuillition of heated 4 hours immediately, concentrate then, and be dissolved in 500mlEA and 500mlH
2Among the O.Leach the precipitation of gained, through being accredited as title compound.Isolate the EA phase, through Na
2SO
4Dry and concentrated.Pass through SiO
2Chromatography is used the EA wash-out, a certain amount of title compound of getting back in addition; Ultimate production is 7.6 grams.
Rf（SiO
2，EA/Hep 1∶1）＝0.2
MS（DCI）：303（M+H）
D) 4 '-bromomethylbiphenyl-2-N, N-dimethylamino formyl radical sulphonamide
Use embodiment 12c) compound, by embodiment 1e) described method prepares title compound.In this method, from 3.8 the gram (13.5 mmole) embodiment 12c) compound can make 1.2 the gram title compounds.
Rf（SiO
2，EA/Hep 2∶1）＝0.2
MS（DCI）：381/383（M+H）
E) 5,7-dimethyl-3-((2 '-N, N-dimethylamino formyl radical sulfonamido biphenyl-4-yl) methyl)-2-ethyl-3H-imidazo (4,5-b) pyridine
Use embodiment 12d) compound and 5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine is by embodiment 9a) described method prepares title compound.From 3.2 gram embodiment 12d) compound can make 1.1 gram title compounds.
Rf（SiO
2，EA/Me OH 10∶1）＝0.2
MS（FAB）：476（M+H）
F) 5,7-dimethyl-2-ethyl-3-((2 '-sulfonamido biphenyl-4-yl) methyl)-3H-imidazo (4,5-b) pyridine
With 0.6 gram (1.26 mmole) embodiment 12e) compound places 20ml ethanol, and with the boiling 45 minutes that refluxes of the dense HCl solution of 10ml.Under vacuum, remove ethanol, the saturated NaHCO of resistates
3The solution neutralization, and use NaHSO
4Solution transfers to about PH5-6, extracts with EA.EA is through Na
2SO
4Drying, and concentrate, 380 milligrams of title compounds obtained.
Rf（SiO
2，EA/Hep 5∶1）＝0.5
MS（FAB）：421（M+H）
G) 5,7-dimethyl-2-ethyl-3-((2 '-ethoxy carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-3H-imidazo (4,5-b) pyridine
Under argon atmospher, with 0.52 gram (1.2 mmole) embodiment 12f) compound and 340 milligrams of K
2CO
3With 266 milligrams of (2.4 mmole) Vinyl chloroformates, 10ml dry DMF reflux 3 hours.Behind the cool to room temperature, mixture 10%NaHSO
4Handle, and extract with EA, organic phase is through MgSO
4Dry.Concentrate, pass through SiO
2Chromatography as eluent, obtains 250 milligrams of title compounds with EA.
Rf（SiO
2，EA）＝0.2
MS（FAB）：493（M+H）
H) 3-((2 '-(amino-ethyl phenyl) carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine
Under argon atmospher, with 80 milligrams of (0.16 mmole) embodiment 12g) compound and 50 μ l phenylethylamines refluxed 1.5 hours with the 5ml dry toluene.Pass through SiO after concentrating
2Chromatography, use EA/MeOH10: 1 wash-out, obtain 70 milligrams of title compounds after the lyophilize, be noncrystalline powder.
Rf（SiO
2，EA/MeOH 10∶1）＝0.4
MS（FAB）：568（M+H）
Embodiment 13
3-((2 '-the amino methyl cyclohexyl) carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine
Use embodiment 12g) compound and cyclohexyl methylamine, by embodiment 12h) described method prepares title compound, and from 80 milligrams of (0.16 mmole) embodiment 12g) compound can make 90 milligrams of title compounds, is an amorphous solid after the lyophilize.
Rf（SiO
2，EA）＝0.3
MS（FAB）：560（M+H）
Embodiment 14
3-((2 '-diallyl amino) carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine
Use embodiment 12g) compound and diallyl amine, by embodiment 12h) described method prepares title compound, and from 80 milligrams of (0.16 mmole) embodiment 12g) compound can make 60 milligrams of title compounds, is amorphous solid.
Rf（SiO
2，EA/MeOH 10∶1）＝0.2
MS（FAB）：544（M+H）
Embodiment 15
3-((2 '-N, N-two allyloxy carbonyl) amino-sulfonyl biphenyl-4-yl) methyl)-5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine
Under argon gas stream, with 100 milligrams of (0.23 mmole) embodiment 12f) compound, 10ml dry DMF and 66 milligrams of (0.46 mmole) K
2CO
3With 57 milligrams of (0.46 mmole) chloroformic acid allyl esters heated and boiled together 45 minutes.After concentrating, it is dissolved among the EA, and uses 10%NaHSO
4Solution washing EA phase is through MgSO
4Drying is passed through SiO
2Chromatography is used the EA wash-out, obtains 70 milligrams of title compounds after the lyophilize.
Rf（SiO
2，EA）＝0.6
MS（FAB）：589（M+H）
Embodiment 16
3-((2 '-(N, N-benzyloxy carbonyl) amino-sulfonyl biphenyl-4-yl) methyl)-5,7-dimethyl-2-ethyl-3H-imidazo (4,5-b) pyridine
Use embodiment 12f) compound and chloroformic acid benzyl ester, prepare this compound by embodiment 15 described methods.From 100 milligrams of (0.23 mmole) embodiment 12f) compound can make 70 milligrams of title compounds.
Rf（SiO
2，EA）＝0.2
MS（FAB）：689（M+H）
Embodiment 17
3-((2 '-(cyclohexyl methoxycarbonyl) amino-sulfonyl biphenyl-4-yl) methyl)-5,7-dimethyl-2-ethyl imidazol(e) is (4,5-b) pyridine also
Use embodiment 12f) compound and chloroformic acid cyclohexyl methyl esters, prepare title compound by embodiment 15 described methods, the acid amides of application and ester such as are at mol ratio.
Rf(SiO
2, t-butyl methyl ether)=0.2
MS（FAB）：561（M+H）
Embodiment 18
5,7-dimethyl-2-ethyl-3-(2 '-(ethoxy carbonyl) amino-sulfonyl biphenyl-4-yl) methyl)-3H-imidazo (4,5-b) pyridine
Use embodiment 12f) compound and Vinyl chloroformate, prepare title compound by embodiment 17 described methods.
Rf（SiO
2，EA）＝0.2
MS（FAB）：493（M+H）
Embodiment 19
2-normal-butyl-1-((2 '-ethoxy carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 2-(the positive pentanoyl of N-()-((2 '-N, N-dimethylamino formyl radical sulfonamido biphenyl-4-yl) methyl)) amino-3-nitrobenzoic acid methyl esters
7.9 gram (28.2 mmole) embodiment 1d) compound and 10.7 gram (28.2 mmole) embodiment 12d) compound, 11.7 restrains (84.6 mmole) K
2CO
3Arise under the room temperature with 200ml dry DMF one and to stir 24 hours.Mixture is concentrated into dried, resistates is dissolved among the EA, EA solution with water washing 3 times, and use 25%KHSO successively
4Solution, saturated NaHCO
3Solution and saturated NaCl solution washing each 1 time are through MgSO
4Drying, and concentrate.The oily resistates obtains 7.9 gram title compounds after with the crystallization of EA/ Di Iso Propyl Ether.Spissated mother liquor passes through SiO
2Chromatography is used normal heptane/EA(2: 3) wash-out, the 2.54 gram title compounds of getting back.
Fusing point: 148-152 ℃
Rf(SiO
2, normal heptane/EA 2: 8)=0.33
MS（FAB）：581（M+H）
B) 2-(the positive pentanoyl of N-()-((2 '-N, N-dimethylamino formyl radical sulfonamido biphenyl-4-yl) methyl) amino-3-Methyl anthranilate
With 10.4 gram (17.9 mmole) embodiment 19a) compound places 800ml methyl alcohol, and hydrogenation is 3 hours in the presence of Raney nickel.The elimination catalyzer is concentrated into filtrate dried, and resistates is dry under high vacuum.Obtain 9.9 gram title compounds, be amorphous foam shape thing.
Rf（SiO
2，CH
2Cl
2/MeOH 95∶5）＝0.3
MS（FAB）：551（M+H）
C) 2-normal-butyl-1-((2 '-sulfonamido biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
With 9.8 gram (17.8 mmole) embodiment 19h) compound is with 90ml concentrated hydrochloric acid and 180ml methyl alcohol stirring and refluxing 3 hours.Evaporating solvent, residual solution transfers to the about 5-6 of pH, aqueous solution CH with 6N NaOH solution
2Cl
2Extract 3 times, the organic phase of merging is with saturated NaCl solution washing, through MgSO
4Dry.Use the EA recrystallization, obtain 8.16 gram title compounds, be white crystal.
Fusing point: 192-195 ℃
Rf(SiO
2, EA/ normal heptane 8: 2)=0.38
MS（FAB）＝478（M+H）
On the other hand, use embodiment 19a) compound, also can make title compound by this law.In the case, from 100 milligrams of (0.19 mmole) embodiment 19a) compound can make 60 milligrams of required compounds.
D) 2-normal-butyl-1-((2 '-dimethylamino formyl radical sulfonamido biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Under argon gas stream, with 150 milligrams of (0.18 mmole) embodiment 19b) compound and saturated EA solution and the 10ml Virahol/EA(1 of 10mlHCl: 1) in kept at room temperature overnight.Enriched mixture, resistates is dissolved in CH
2Cl
2In, CH
2Cl
2Use saturated Na mutually successively
2CO
3Solution, water and saturated NaCl solution washing are through MgSO
4Drying, concentrated and dry under high vacuum, obtain 138 milligrams of title compounds, be amorphous foam shape thing.
Rf（SiO
2，CH
2Cl
2/MeOH 95∶5）＝0.5
MA（FAB）：533（M+H）
E) 2-normal-butyl-1-((2 '-ethoxy carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
With 3.25 gram (6.81 mmole) embodiment 19c) compound and 170 milligrams of (1.36 mmole) DMAP place the 12ml anhydrous pyridine, under argon gas stream, handle with 1.53 gram (13.6 mmole) uncle's potassium butyrates in 0 ℃, after stirring 10 minutes under the same temperature, use the 0.65ml(6.81 mmole) the Vinyl chloroformate processing.This mixture stirs under room temperature and spends the night.Then ice-cooled following with solution 25%KHSO
4Solution is regulated, and until acid-reaction occurring, and uses the EA extracted several times.The organic phase that merges is with saturated NaCl solution washing, through MgSO
4Drying, and concentrate.Pass through SiO
2Chromatography is used CH
2Cl
2/ MeOH/NH
3(9: 1: 0.1) wash-out obtains 1.8 gram title compounds, is amorphous foam shape thing.
Rf（SiO
2，CH
2Cl
2/MeOH/HoAc 9∶1∶0.2）＝0.71
MS（FAB）：550（M+H）
F) 2-normal-butyl-1-((2 '-ethoxy carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Use embodiment 19e) compound, by embodiment 1h) described method prepares title compound.
Rf（SiO，CH Cl/MeOH/HOAc 9∶1∶0.2）＝0.64
MS（FAB）：536（M+H）
Embodiment 20
2-normal-butyl-1-((2 '-n-propylamine base carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 2-normal-butyl-1-((2 '-n-propylamine base carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
With 100 milligrams of (0.21 mmole) embodiment 19c) compound places the 8ml anhydrous propanone, and with 90 milligrams of (0.6 mmole) K
2CO
3With 24 μ l(0.25 mmoles) propyl isocyanate boiling reflux 2 hours together.It is about 1 that cooling back solution is adjusted to pH with 2N HCl, uses CH
2Cl
2Extracted several times.The organic phase that merges is used H successively
2O and saturated NaCl solution washing each once, through MgSO
4Drying, and concentrate.Use the EA recrystallization, obtain 107 milligrams of title compounds.
Fusing point: 150-152 ℃
Rf（SiO
2，CH
2Cl
2/MeOH/NH
39∶1∶0.2）＝0.24
MS（FAB）：563（M+H）
B) 2-normal-butyl-1-((2 '-n-propylamine base carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Use embodiment 20a) compound, by embodiment 1h) described method prepares title compound.From 38 milligrams of (0.07 mmole) embodiment 20a) compound can make 30 milligrams of required compounds, is amorphous foam shape thing.
Rf（SiO
2，CH
2Cl
2/MeOH/AcOH 9∶1∶0.2）＝0.2
MS（FAB）：549（M+H）
Embodiment 21
2-normal-butyl-1-((2 '-isopropyl amino-carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
206 milligrams of (0.38 mmole) embodiment 19e) compound and 5ml Isopropylamine and 50ml toluene place autoclave, and in 80 ℃ of reactions 8 hours.Reaction solution is concentrated, and resistates passes through SiO
2Chromatography is used CH
2Cl
2/ MeOH(95: 5) wash-out.Obtain 38 milligrams of title compounds, be amorphous foam shape thing.
Rf（SiO
2，CH
2Cl
2/MeOH/AcOH 9∶1∶0.2）＝0.35
MS（FAB）：549（M+H）
Embodiment 22
2-normal-butyl-1-((2 '-allyl amino carbonyl amino alkylsulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 2-normal-butyl-1-((2 '-allyl amino carbonyl amino alkylsulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Use embodiment 19c) compound, press embodiment 20a) described method, replace propyl isocyanate to prepare title compound with allyl isocyanate.From 150 milligrams of (0.31 mmole) embodiment 19c) compound can make 136 milligrams of title compounds.
Fusing point: 142-145 ℃
Rf（SiO
2，CH
2Cl
2/MeOH/NH 9∶1∶0.2）＝0.19
MS（FAB）：561（M+H）
B) 2-normal-butyl-1-((2 '-allyl amino carbonyl amino alkylsulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
With 123 milligrams of (0.22 mmole) embodiment 22a) compound, press embodiment 1h) described method preparation, get 73 milligrams of title compounds.
Fusing point: 220 ℃
Rf（SiO
2，CH
2Cl
2/MeOH/AcOH 9∶1∶0.2）＝0.35
MS（FAB）：547（M+H）
Embodiment 23
2-normal-butyl-1-((2 '-B aminocarbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 2-normal-butyl-1-((2 '-B aminocarbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Use embodiment 19c) compound and ethyl isocyanate, by embodiment 20a) described method prepares title compound.
Fusing point: 182 ℃
Rf（SiO
2，CH
2Cl
2/MeOH/NH
39∶1∶0.2）＝0.22
MS（FAB）：549（M+H）
B) 2-normal-butyl-1-((2 '-B aminocarbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
Use embodiment 23a) compound, by embodiment 1h) described method prepares this compound.
Fusing point:＞220 ℃
Rf（SiO
2，CH
2Cl
2/MeOH/HOAc 9∶1∶0.2）＝0.35
MS（FAB）：535（M+H）
Embodiment 24
2-normal-butyl-1-((2 '-cyclopropyl amino-carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
A) 2-normal-butyl-1-((2 '-cyclopropyl amino-carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylate methyl ester
Under argon gas stream, in 80 ℃ with 139 milligrams of (0.29 mmole) embodiment 19c) compound and 35 milligrams of (0.88 mmole) powdery NaOH, 67 milligrams of (0.32 mmoles) 2,2,2-three chloro-N-cyclopropyl methylacetamides (being made by cyclopropyl-methylamine and trichoroacetic chloride) and the anhydrous DMSO of 2ml stirred 30 minutes together.Reaction solution is poured in the ice, and with 2N HCl acidifying, the precipitation that suction filtration is separated out.Behind the EA recrystallization, obtain 69 milligrams of title compounds.
Fusing point: 158-161 ℃
Rf(SiO
2, normal heptane/EA 2: 8)=0.23
MS（FAB）：575（M+H）
B) 2-normal-butyl-1-((2 '-cyclopropyl amino-carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-1H-benzoglyoxaline-7-carboxylic acid
Use embodiment 24a) compound, by embodiment 1h) described method prepares title compound.
Fusing point: 234-236 ℃
Rf（SiO
2，CH
2Cl
2/MeOH/HOAc 9∶1∶0.2）＝0.28
MS（FAB）：561（M+H）
Embodiment 25
2-normal-butyl-3-((2 '-ethoxy carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-3H-imidazo-(4,5-b)/(5,4-b) pyridine
A) 2-normal-butyl-3-((2 '-N, N-dimethylamino formyl radical sulfonamido biphenyl-4-yl) methyl)-3H-imidazo (4,5-b)/(5,4-b) pyridine
Use embodiment 4a) and 12d) compound, by embodiment 4b) described method prepares title compound.Pass through SiO
2Chromatography purification, usefulness EA/MeOH as eluent uses EA/ Di Iso Propyl Ether crystallization at 20: 1.
Fusing point: 205-211 ℃
Rf（SiO
2，EA/MeOH 20∶1）＝0.15
MS（FAB）：476（M+H）
B) 2-normal-butyl-3-((2 '-sulfonamido biphenyl-4-yl) methyl)-3H-imidazo (4,5-b)/(5,4-b) pyridine
Use embodiment 25a) compound, by embodiment 19c) described method prepares title compound, passes through SiO
2Chromatography, with EA/MeOH 20: 1 as eluent.
Rf（SiO
2，EA/MeOH 20∶1）＝0.39
MS（FAB）：421（M+H）
C) 2-normal-butyl-3-((2 '-ethoxy carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-3H-imidazo-(4,5-b)/(5,4-b) pyridine
Under argon atmospher, with 1 gram (2.38 mmole) embodiment 25b) compound and 1 gram activatory 4
Molecular sieve (in 150 ℃ of high vacuum dry 3 hours), 0.66 gram K
2CO
3, 232 μ l Vinyl chloroformates and 25ml anhydrous dimethyl oxygen base ethane reflux 6 hours together.Cooling back mixture 100ml 10%KH
2PO
4Solution (pH about 4) is handled, and with EA extraction 3 times, the EA extraction liquid of merging is through Na
2SO
4Drying, and concentrate.Pass through SiO
2Chromatography (20: 1 wash-outs of EA/MeOH) obtains 0.5 gram title compound
Fusing point: 172 ℃
Rf（SiO
2，EA/MeOH 20∶1）＝0.3
MS（FAB）：493（M+H）
Embodiment 26
2-normal-butyl-3-((2 '-isopropyl amino-carbonyl amino-sulfonyl biphenyl-4-yl) methyl)-3H-imidazo (4,5-b)/(5,4-b) pyridine
With 100 milligrams of (0.2 mmole) embodiment 25c) compound is with 209 μ l(2.44 mmoles) Isopropylamine and 5ml toluene boiling reflux 3 hours.Through concentrating and SiO
2Chromatography (EA wash-out) obtains 45 milligrams of title compounds.
Fusing point: 113-114 ℃
Rf（SiO
2，EA/MeOH 20∶1）＝0.36
MS（FAB）：506（M+H）
Embodiment 27
2-normal-butyl-3-((2 '-allyl amino carbonyl amino alkylsulfonyl biphenyl-4-yl) methyl)-3H-imidazo (4,5-b)/(5,4-b) pyridine
Use embodiment 25b) compound and allyl isocyanate, by embodiment 20a) described similar method prepares title compound.
Fusing point: 121 ℃
Rf（SiO
2，EA/MeOH 20∶1）＝0.26
MS（FAB）：504（M+H）
Embodiment 28
2-normal-butyl-3-((2 '-n-propylamine base carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-3H-imidazo (4,5-b)/(5,4-b) pyridine
With 150 milligrams of (0.3 mmole) embodiment 25c) compound is with 295 μ l(3.6 mmoles) Tri N-Propyl Amine and 5ml toluene boiling reflux 3 hours.Enriched mixture, resistates passes through SiO
2Chromatography (EA wash-out).Obtain 90 milligrams of title compounds.
Fusing point: 137-138 ℃
Rf（SiO
2，EA）＝0.2
MS（FAB）：506（M+H）
Embodiment 29
2-normal-butyl-3-((2 '-benzyloxycarbonyl amino-sulfonyl biphenyl-4-yl) methyl)-3H-imidazo (4,5-b)/(5,4-b) pyridine
Use embodiment 25b) compound and chloroformic acid benzyl ester, by embodiment 25c) described method prepares title compound.
Fusing point: 85 ℃
Rf（SiO
2，EA/MeOH 20∶1）＝0.29
MS（FAB）：555（M+H）
Embodiment 30
2-ethyl-7-methyl-3-((2 '-n-propylamine base carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-imidazo-(4,5-b) pyridine
A) 2-ethyl-7-methyl-3H-imidazo (4,5-b) pyridine
10 gram (65.3 mmole) 2-amino-4-methyl-3-nitro-pyridines are placed 40ml tetrahydrofuran (THF) and 40ml methyl alcohol, and carry out hydrogenation in the presence of Raney nickel.Filtration catalizer, evaporating solvent, resistates is handled with the HCl-ethanolic soln, suction filtration separate out 2,3-diamino-4-picoline hydrochloride.7 these hydrochlorides of gram are dissolved in 57 gram Tripyrophosphoric acid (with 28.5 gram P
2O
5With 28.5 gram H
3PO
4(concentration is 85%) makes) in, and handle with the 1.26ml propionic acid, this solution stirred 2 hours in 100 ℃.After the cooling, be poured in the frozen water, and add Na
2CO
3The EA extracted several times is used in alkalization.The EA that merges uses saturated NaCl solution washing mutually, through Na
2SO
4Dry and concentrated, resistates passes through SiO
2Chromatography (5: 1 wash-outs of EA/MeOH).Obtain 4.2 gram title compounds.
Rf（SiO
2，EA/MeOH 5∶1）＝0.4
MS（DCl）：162（M+H）
B) 3-((2 '-N, N-dimethylamino formyl radical sulfonamido biphenyl-4-yl) methyl)-2-ethyl-7-methyl-imidazo (4,5-b) pyridine
With 3.1 gram (19.26 mmole) embodiment 30a) compound and 9.15 gram (19.26 mmole) embodiment 12d) compound (concentration is 75%) places the 200ml dry DMF, at 2.6 gram (19.6 mmole) K
2CO
3Exist down in stirred overnight at room temperature.Remove and desolvate, resistates is dissolved in CH
2Cl
2In, CH
2Cl
2Solution H
2The O washing is through Na
2SO
4Dry and concentrated.Pass through SiO
2Chromatography (20: 1 wash-outs of EA/MeOH) obtains 2.8 gram title compounds.
Fusing point: 168-170 ℃
Rf（EA/MeOH 20∶1）＝0.13
MS（FAB）：462（M+H）
C) 2-ethyl-7-methyl-3-((2 '-sulfonamido biphenyl-4-yl) methyl)-imidazo-(4,5-b) pyridine
With 2.8 gram (6.06 mmole) embodiment 30b) compound is by embodiment 19c) described method is transformed into title compound (2.2 restrain).
Fusing point: 211-212 ℃
Rf（SiO
2，EA/MeOH）＝0.35
MS（FAB）：407（M+H）
D) 2-ethyl-7-methyl-3-((2 '-n-propylamine base carbonylamino alkylsulfonyl biphenyl-4-yl) methyl)-imidazo (4,5-b) pyridine
Use embodiment 30c) compound and propyl isocyanate, by embodiment 20a) described method prepares title compound.With 70 milligrams of (0.172 mmole) compound 30c) can obtain 43 milligrams of required products.
Fusing point: 215-220 ℃
Rf（SiO
2，EA/MeOH 20∶1）＝0.36
MS（FAB）：492（M+H）
Embodiment 31
2-ethyl-3-((2 '-B aminocarbonyl amino-sulfonyl biphenyl-4-yl) methyl)-7-methyl-imidazo (4,5-b) pyridine
Use embodiment 30c) compound and ethyl isocyanate, by embodiment 20a) described method prepares title compound.
Fusing point: 240-245 ℃
Rf（SiO
2，EA）＝0.14
MS（FAB）：478（M+H）
Embodiment 32
3-((2 '-allyl amino carbonyl amino alkylsulfonyl biphenyl-4-yl) methyl)-2-ethyl-7-methyl-imidazo (4,5-b) pyridine
Use embodiment 30c) compound and allyl isocyanate, by embodiment 20a) described method reacts, the preparation title compound.
Fusing point: 216-219 ℃
Rf（SiO
2，EA）＝0.13
MS（FAB）：490（M+H）
Embodiment 33
2-ethyl-3-((2 '-methoxycarbonyl amino-sulfonyl biphenyl-4-yl) methyl)-7-methyl-imidazo (4,5-b) pyridine
With 100 milligrams of (0.245 mmole) embodiment 30c) compound and 171 milligrams of (1.24 mmole) K
2CO
3, the 62ul(0.62 mmole) dimethyl carbonic acid hydrogen ester, 25 milligrams of DMAP and 10ml diglyme stirring and refluxing 2 hours together.Steam then and desolventize resistates EA/KH
2PO
4Solution-treated is separated organic phase, and is used KH
2PO
4Solution washing 2 times.Through Na
2SO
4Dry, concentrate and pass through SiO
2Chromatography (EA wash-out) obtains 44 milligrams of title compounds.
Rf（SiO
2，EA）＝0.15
MS（FAB）：465（M+H）
Prepare the V of formula shown in following table embodiment compound by the similar structural unit of the foregoing description 1-33 method:
Claims (4)
1, the method for the salt that can tolerate on preparation formula I compound and the physiology thereof,
Wherein each symbol has following meaning:
X is the bicyclic group that the monocycle base of 3,4 or 5 annular atomses is arranged or 8-10 annular atoms arranged, and monocycle base or bicyclic group can completely or partially be hydrogenated, wherein CH more than 1 or 1 or CH
2Group can be replaced by N, NH or O;
R (1) is: 1. (C
1-C
10) alkyl
2. (C
3-C
10) alkenyl,
3. (C
3-C
10) alkynyl,
4.OR(6)，
5. (C
3-C
8) cycloalkyl,
6. (C
4-C
10) cycloalkylalkyl,
7. (C
5-C
10) the cycloalkyl alkenyl,
8. (C
5-C
10) the cycloalkyl alkynyl,
9.(CH
2)m-B-(CH
2)n-R(7)，
10. benzyl,
11. the group of definition in top 1,2,3 or 9, this group is by CO
2R (6) is single to be replaced,
12. the group of definition in top 1,2,3 or 9, wherein 1～all hydrogen atoms are replaced by fluorine, perhaps
13. the group of definition in top 10 replaces by being selected from 1 of following series or 2 identical or different groups on the phenyl of this group: halogen, (C
1-C
4) alkoxyl group and nitro;
R (2), R (3), R (4) and R (5) can be identical or different, and they are
1. hydrogen, halogen, hydroxyl, cyano group, nitro, sulfo group, formyl radical, benzoyl, (C
1-C
8) acyl group, (C
1-C
8) acyloxy, sulfydryl, carboxyl, (C
1-C
4) alkoxy carbonyl,
2. alkyl, alkenyl, alkoxyl group or allyl sulfenyl straight or branched, that replace arbitrarily up to 6 carbon atoms are arranged,
3. aryl, aralkyl or aromatic yl alkenyl, wherein alkyl and alkenyl substitutents have up to 6 carbon atoms and are the form of non-side chain or side chain, aryl substituent is that the monocyclic groups of 5 or 6 annular atomses is arranged or is the fused rings that 8-14 annular atoms arranged, wherein contain 1 or 1 above heteroatoms (as O, N or S), and at random be substituted
R (6) is 1. hydrogen,
2. (C
1-C
8) alkyl,
3. (C
3-C
8) cycloalkyl,
4. phenyl,
5. benzyl, perhaps
6. the group of definition in top 2, wherein 1～all hydrogen atoms are replaced by fluorine
R (7) is 1. hydrogen,
2. (C
1-C
6) alkyl
3. (C
3-C
8) cycloalkyl
4. (C
2-C
4) alkenyl, or
5. (C
2-C
4) alkynyl;
R (8) and R (9) or R (10) and R (11) or identical, or different, they can be
1. hydrogen,
2. (C
1-C
6) alkyl or (C
1-C
6) alkenyl, can be unsubstituted, perhaps by halogen, hydroxyl or (C
1-C
6) the alkoxyl group replacement,
3. aryl or (C
1-C
6) alkylaryl, wherein aryl is the monocycle that 5 or 6 annular atomses are arranged, perhaps for the dicyclo of 8-10 annular atoms is arranged, monocycle or dicyclo at random contain the heteroatoms (as O, N and S) more than 1 or 1, and can replace by being selected from 1 of following series or 2 identical or different groups: halogen, hydroxyl, nitro, (C
1-C
6) alkyl, (C
1-C
6) alkenyl, (C
1-C
4) alkanoyl, (C
1-C
4) alkanoyloxy and CO
2R
6Perhaps
R (8) forms quaternary one eight yuan saturated or undersaturated rings with R (11) with the nitrogen-atoms that is connected them with R (9) or R (10), this ring can contain the other heteroatoms that is selected from N, O and S, and this ring can be unsubstituted, perhaps by halogen, hydroxyl, (C
1-C
4) alkyl, (C
1-C
4) alkenyl, (C
1-C
4) alkoxyl group and CO
2R (6) replaces, perhaps
R (10) is identical or inequality with R (11), can be acyl group or the (C that has up to 6 carbon atoms
1-C
6) alkyl or (C
6-C
12) aryl, they can be at random by halogen or (C
1-C
6) the alkyl replacement; L is (C
1-C
3) alkane 2 basis;
R (12) and R (13) are identical or different, can be
1. hydrogen,
2. halogen,
3. nitro,
4. (C
1-C
4) alkyl, perhaps
5. (C
1-C
2) alkoxyl group;
Q is zero or 1;
A 1. has the heterocyclic radical of 5-10 annular atoms, this heterocycle can be monocycle or dicyclo, and having up to 9 annular atomses in the heterocycle is carbon atoms, and this heterocyclic radical can be unsubstituted, perhaps by replacing, perhaps up to 6 (preferably up to 3) identical or different radicals R (14) and R (15)
2. unsubstituted or by the xenyl that replaces up to 4 (preferably up to 2) identical or different radicals R (14) and R (15), but herein A must be at least by 1 R (15) 18,19,28,40 or 42 in the group of definition replace, and q is zero,
R (14) is 1. halogens
2. oxygen,
3. nitroso-group,
4. nitro
5. amino
6. cyano group
7. hydroxyl
8. (C
1-C
6) alkyl
9. (C
1-C
4) alkanoyl
10. (C
1-C
4) alkanoyloxy
11.CO
2R(6)
12. methanesulfonamido
13. fluoroform sulfonamido
14.-CO-NH-OR(16)
15.-SO
2-NR(17)R(18)，
16.-CH
2-OR(18)，
17. (C
1-C
4) heteroaryl-(CH
2) q-, 1-tetrazyl preferably,
18. (C
7-C
13) aroyl,
21. (C
6-C
12) aryl;
R (15) is 1. hydrogen,
2. (C
1-C
6) alkyl,
3. (C
3-C
8) cycloalkyl,
4. (C
6-C
12) aryl,
5. (C
7-C
13) aroyl,
6. (C
1-C
4) alkoxyl group,
7. (C
1-C
4) alkanoyloxy,
8. (C
1-C
9) heteroaryl,
9.CO
2R(6)，
10. halogen
11. cyano group,
12. nitro,
13.NR(17)R(18)
14. hydroxyl,
15.-CO-NH-CHR(19)-COR(6)，
16. sulfo group,
17.-SO
3R(6)，
18.-SO
2-NR (18)-CO-NR (17) R (16) ,-SO
2-NR (18)-CO-O-R (17) ,-SO
2N (CO-O-R (17)
2Or-SO
2-NR (18)-CS-NR (17) R (16),
19.-NR(18)CO-NR(17)-SO
2-CH
2-R(18)，
20.-C(CF
3)
2OH，
21. phosphonato,
22.-PO
3H
2，
23.-NH-PO(OH)
2，
24.-S(O)rR(17)，
25.-CO-R(20)，
26.-CO-NR(17)R(16)，
27.
28.
29.
，
30.
，
31.5-tetrazyl-NH-CO-,
32.-CO-NH-NH-SO
2-CF
3，
33.
39.-CO-NH-SO
2-R(6)，
40.-SO
2-NH-CO-R(17)，
41. the group of definition in 4, this group can replace by being selected from 1 of following series or 2 identical or different groups: halogen, cyano group, nitro, NR (17) R (18) and hydroxyl,
42.R (15) with R (14) formation-CO-NH-SO
2-;
R (16) and R (17) are identical or different, and they are
1. hydrogen,
2. (C
1-C
6) alkyl,
3. (C
3-C
8) cycloalkyl,
4. (C
6-C
12) aryl, phenyl preferably,
5. (C
6-C
10) aryl-(C
1-C
4) alkyl,
6. part or all of hydrogenant (C
1-C
9) heteroaryl, preferably 2-pyrimidyl, piperidino or quinuclidinyl,
7. (C
3-C
6) alkanoyl,
8. by 1 or 2 identical or different group that is selected from following series: hydroxyl, methoxyl group, nitro, cyano group, CO
2R (6), trifluoromethyl ,-NR (25) R (26) and
What replace is defined in group in 4,5,6,9,14,15,16,18,19 or 20,
9. (C
1-C
9) heteroaryl-(C
1-C
3) alkyl, heteroaryl moieties can partly or entirely be hydrogenated here.
10.2 the group of middle definition, wherein 1-all hydrogen atom is replaced by fluorine,
11. (C
2-C
6) alkenyl,
12. (C
3-C
8) cycloalkenyl,
13. (C
3-C
8) cycloalkenyl-(C
1-C
3) alkyl,
14. (C
3-C
8) cycloalkyl-(C
1-C
4) alkyl,
15. (C
6-C
10) aryl-(C
3-C
6) alkenyl,
16. (C
1-C
9) heteroaryl-(C
3-C
6) alkenyl,
17. (C
3-C
6) alkynyl,
18. (C
6-C
10) aryl-(C
3-C
6) alkynyl,
19. (C
1-C
9) heteroaryl-(C
3-C
6) alkynyl,
20. formula
Group, can not there be stereocenter in R in the formula (16) for defining 20, perhaps is the R-configuration, perhaps is the S-configuration.
21.R (16) R (17) forms heteroaryl with the nitrogen-atoms that connects them, this heteroaryl is partly or entirely hydrogenation also;
R (18) is 1. hydrogen,
2. (C
1-C
6) alkyl,
3. (C
3-C
8) cycloalkyl,
4. (C
6-C
12) aryl-(C
1-C
6) alkyl, benzyl preferably,
5. benzyl, or
6. (C
1-C
9) heteroaryl,
R (19) is 1. hydrogen,
2. (C
1-C
6) alkyl,
3. (C
3-C
8) cycloalkyl,
4. phenyl, or
5. benzyl;
R (20) is 1. hydrogen,
2. (C
1-C
6) alkyl,
3. (C
3-C
8) cycloalkyl,
4. phenyl-(CH
2) q-,
5.OR(19)，
6.NR (25) R (26), or
7.
R (21) is cyano group, nitro or CO
2R (18);
R (22) is CO
2R (6) or CH
2CO
2R (6);
R (23) is hydrogen, halogen, (C
1-C
4) alkyl or (C
1-C
4) alkoxyl group;
R (24) is hydrogen, (C
1-C
4) alkyl or phenyl;
R (25) and R (26) are identical or different, can be
1. hydrogen,
2. (C
1-C
4) alkyl,
3. phenyl,
4. benzyl, or
5. α-Jia Jibianji;
D is NR (23), O or CH
2
B is O, NR (18) or S;
T is 1. singly-bounds,
2.-CO-，
3.-CH
2-，
4.-O-，
5.-S-，
6.-NR(28)-，
7.-CO-NR(28)-，
8.-NR(28)-CO-，
9.-O-CH
2-，
10.-CH
2-O-，
11.-S-CH
2-，
12.-CH
2-S-，
13.-NH-CR(27)R(29)-，
14.-NR(28)-SO
2-，
15.-SO
2-NR(28)-，
16.-CR(27)R(29)-NH-，
17.-CH=CH-，
18.-CF=CF-，
19.-CH=CF-，
20.-CF-CH-，
21.-CH
2-CH
2-，
22.-CF
2-CF
2-，
23.-CH(OR(6))-，
24.-CH(OCOR(19))-，
R (27) and R (29) are identical or different, can be hydrogen, (C
1-C
5) alkyl, phenyl, allyl group or benzyl;
R (28) is hydrogen, (C
1-C
6) alkyl, benzyl or allyl group;
R (30) is 1.NR (27) R (28),
2. urea groups,
3. thioureido,
4. toluene-4-alkylsulfonyl, or
5. phenylsulfonamido;
R (31) and R (32) can be identical or different, can be (C
1-C
4) alkyl, perhaps R (31) and R (32) are-(CH together
2) q-;
Q is CH
2, NH, O or S;
N is integer 1-5;
M is integer 0-3;
O is integer 1-10;
R is zero, 1 or 2,
This method comprises carries out alkylation with the formula III compound with the formula IV compound, in addition, at random sloughs the protecting group of interim introducing, and at random the formula I compound that obtains is transformed into the salt that can tolerate on its physiology,
Wherein the definition of R (1), R (2), R (3), R (4), R (5) and X is the same,
Wherein the definition of L, q, R (12), R (13) and A is the same, and U is a leavings group.
2, the method that has the formula I compound of formula II by the described preparation of claim 1,
Each symbol has following meaning in the formula:
Z(1), Z(3 Z(2)) and Z(4) be
1.-CH
2-，
2.-CH＝，
3. the group of definition in 2, wherein 1 or 2 methyne groups are replaced by nitrogen, Z(4)=N is better,
R(1) be 1.(C
1-C
10) alkyl,
2.(C
3-C
10) alkenyl,
3.(C
3-C
10) alkynyl,
4.(C
3-C
8) cycloalkyl,
5. benzyl, perhaps
6. the benzyl that replaces as previously discussed;
R(2) and R(3) be identical or different, can be
1. hydrogen,
2. hydroxyl
3. halogen
4. do not replace or by identical or different halogen, the hydroxyl, (C of being selected from more than 1 or 1
1-C
4) alkoxyl group, (C
1-C
4) straight or branched (C that replaces of alkylthio and sulfydryl substituting group
1-C
6) alkyl;
5.-CO
2R（6）;
T be singly-bound ,-O-,-CO-,-NHCO-or-OCH
2-, above definition is seen in other groups and variation thereof.
3, the method for preparing the described formula II compound of claim 2, each symbol has following meaning in the formula:
R(1) be (C
1-C
7) alkyl, (C
3-C
7) alkenyl or (C
3-C
7) alkynyl;
R(6) be hydrogen or (C
1-C
4) alkyl;
Q is 0 or 1;
R(12) and R(13) being identical or different, can be hydrogen or (C
1-C
4) alkyl;
R(14) be 1.(C
1-C
4) alkyl,
2.(C
1-C
4) alkoxyl group,
3. cyano group,
4. amino,
5. nitro,
6. fluorine, chlorine or bromine,
7.(C
1-C
4) heteroaryl-CH
2,
8.(C
1-C
4) alkanoyloxy,
9.(C
1-C
4) alkanoyl
Benzoyl or
11. tetrazyl;
R(15) be 1.(C
1-C
4) alkyl
2.(C
6-C
12) aryl
3.(C
1-C
3) alkanoyloxy
4.(C
1-C
4) alkoxyl group
5.(C
1-C
9) heteroaryl, 5-tetrazyl preferably,
6. cyano group,
7. nitro,
8. hydroxyl,
9.SO
3R（6），
10. chlorine, bromine,
11.CO
2R（6），
12.CO-NH-R（19），
13.CO-R（20），
14.SO
2-NR（18）-CO-NR（17）R（16），
15.SO
2Or SO NR(18)-CO-O-R(17)
2N(CO-OR(17))
2,
16.CO-CHR（19）-CO
2H，
17.(C
1-C
4) alkyl-CO
2H,
18.NH-CH-NH-SO
2-CH
2-R（19），
20.
21.
22.
Or
23.R(14) with R(15) formation-CH-NH-SO
2;
L is-CH
2-;
R(18) be hydrogen;
R(25) and R(26) be hydrogen or (C independently of each other
1-C
4) alkyl, and wherein other substituting groups and symbol with claim 2.
4, the medicine of the application rights formula I compound that requires 1 described method to make with angiotensin-ii-receptor antagonistic action.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4130659 | 1991-09-14 | ||
| DEP4130659.7 | 1991-09-14 | ||
| DEP4131325.9 | 1991-09-20 | ||
| DE19914131325 DE4131325A1 (en) | 1991-09-20 | 1991-09-20 | New fused imidazole derivs are angiotensin II antagonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1070646A true CN1070646A (en) | 1993-04-07 |
Family
ID=25907347
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN92110562A Pending CN1070646A (en) | 1991-09-14 | 1992-09-12 | Imidazo-fused iso and heterocycle, their preparation method contains their composition and their application |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US5444068A (en) |
| EP (1) | EP0533058B1 (en) |
| JP (1) | JP3459659B2 (en) |
| KR (1) | KR930006020A (en) |
| CN (1) | CN1070646A (en) |
| AT (1) | ATE247644T1 (en) |
| AU (1) | AU659485B2 (en) |
| BR (1) | BR9203543A (en) |
| CA (1) | CA2078058A1 (en) |
| CZ (1) | CZ280492A3 (en) |
| DE (1) | DE59209986D1 (en) |
| DK (1) | DK0533058T3 (en) |
| ES (1) | ES2204888T3 (en) |
| FI (1) | FI924054A (en) |
| HU (1) | HUT62892A (en) |
| IL (1) | IL103141A0 (en) |
| NO (1) | NO300326B1 (en) |
| NZ (1) | NZ244303A (en) |
| PL (1) | PL171766B1 (en) |
| PT (1) | PT533058E (en) |
| RU (1) | RU2076105C1 (en) |
| TW (1) | TW300219B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1054377C (en) * | 1993-08-05 | 2000-07-12 | 鲁索-艾克勒夫公司 | New bicyclic derivatives of imidazole, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them |
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-
1992
- 1992-03-07 TW TW081101731A patent/TW300219B/zh active
- 1992-09-10 EP EP92115500A patent/EP0533058B1/en not_active Expired - Lifetime
- 1992-09-10 FI FI924054A patent/FI924054A/en not_active Application Discontinuation
- 1992-09-10 PT PT92115500T patent/PT533058E/en unknown
- 1992-09-10 AT AT92115500T patent/ATE247644T1/en active
- 1992-09-10 ES ES92115500T patent/ES2204888T3/en not_active Expired - Lifetime
- 1992-09-10 DE DE59209986T patent/DE59209986D1/en not_active Expired - Lifetime
- 1992-09-10 DK DK92115500T patent/DK0533058T3/en active
- 1992-09-11 CA CA002078058A patent/CA2078058A1/en not_active Abandoned
- 1992-09-11 PL PL92295911A patent/PL171766B1/en unknown
- 1992-09-11 JP JP24346992A patent/JP3459659B2/en not_active Expired - Lifetime
- 1992-09-11 CZ CS922804A patent/CZ280492A3/en unknown
- 1992-09-11 NO NO923535A patent/NO300326B1/en unknown
- 1992-09-11 NZ NZ244303A patent/NZ244303A/en unknown
- 1992-09-11 RU SU925053022A patent/RU2076105C1/en active
- 1992-09-11 IL IL103141A patent/IL103141A0/en unknown
- 1992-09-11 AU AU23533/92A patent/AU659485B2/en not_active Ceased
- 1992-09-11 BR BR929203543A patent/BR9203543A/en not_active Application Discontinuation
- 1992-09-12 CN CN92110562A patent/CN1070646A/en active Pending
- 1992-09-14 KR KR1019920016634A patent/KR930006020A/en not_active Application Discontinuation
- 1992-09-14 HU HU9202931A patent/HUT62892A/en unknown
-
1993
- 1993-12-13 US US08/165,655 patent/US5444068A/en not_active Expired - Lifetime
-
1995
- 1995-06-05 US US08/463,299 patent/US5635525A/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1054377C (en) * | 1993-08-05 | 2000-07-12 | 鲁索-艾克勒夫公司 | New bicyclic derivatives of imidazole, their preparation process, the new intermediates obtained, their use as medicaments and the pharmaceutical compositions containing them |
Also Published As
| Publication number | Publication date |
|---|---|
| DE59209986D1 (en) | 2003-09-25 |
| PL295911A1 (en) | 1993-03-22 |
| NO300326B1 (en) | 1997-05-12 |
| AU2353392A (en) | 1993-03-18 |
| TW300219B (en) | 1997-03-11 |
| ATE247644T1 (en) | 2003-09-15 |
| JPH05262742A (en) | 1993-10-12 |
| KR930006020A (en) | 1993-04-20 |
| EP0533058A1 (en) | 1993-03-24 |
| BR9203543A (en) | 1993-04-13 |
| IL103141A0 (en) | 1993-02-21 |
| US5444068A (en) | 1995-08-22 |
| RU2076105C1 (en) | 1997-03-27 |
| CA2078058A1 (en) | 1993-03-15 |
| FI924054A (en) | 1993-03-15 |
| NO923535L (en) | 1993-03-15 |
| HU9202931D0 (en) | 1992-11-30 |
| ES2204888T3 (en) | 2004-05-01 |
| JP3459659B2 (en) | 2003-10-20 |
| EP0533058B1 (en) | 2003-08-20 |
| CZ280492A3 (en) | 1993-04-14 |
| US5635525A (en) | 1997-06-03 |
| AU659485B2 (en) | 1995-05-18 |
| NZ244303A (en) | 1995-12-21 |
| HUT62892A (en) | 1993-06-28 |
| FI924054A0 (en) | 1992-09-10 |
| NO923535D0 (en) | 1992-09-11 |
| PT533058E (en) | 2004-01-30 |
| PL171766B1 (en) | 1997-06-30 |
| DK0533058T3 (en) | 2003-11-24 |
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